Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl.C(N=C=NCCCN(C)C)C.[CH3:29][C:30]([CH3:65])([CH3:64])/[CH:31]=[CH:32]/[C@H:33]1[O:38][C:37]([CH3:40])([CH3:39])[O:36][C@@H:35]([C@@H:41]([O:61][CH3:62])[C:42]([NH:44][C@H:45]2[CH2:51][CH2:50][C@@H:49](O)[CH2:48][N:47]([CH2:53][C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[C:46]2=[O:60])=[O:43])[C@@H:34]1[OH:63]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:29][C:30]([CH3:65])([CH3:64])/[CH:31]=[CH:32]/[C@H:33]1[O:38][C:37]([CH3:39])([CH3:40])[O:36][C@@H:35]([C@@H:41]([O:61][CH3:62])[C:42]([NH:44][C@@H:45]2[C:46](=[O:60])[N:47]([CH2:53][C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH2:48][C@H:49]([O:15][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:50][CH2:51]2)=[O:43])[C@@H:34]1[OH:63]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CO[C@@H](C(=O)N[C@H]1CC[C@@H](O)CN(Cc2cccnc2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)O[C@@H]1CC[C@H](NC(=O)[C@H](OC)[C@@H]2OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]2O)C(=O)N(Cc2cccnc2)C1
Reaction time: 16 h
Yield: 29.4 %

Procedure:
To a stirred solution of tetradecanoic acid (0.39 g 1.7 mmol) and 4-dimethylaminopyridine (0.21 g, 1.7 mmol) in CH2Cl2(15 mL) is added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride (0.34 g, 1.7 mmol) at room temperature. After 30 min (R)-2-[(4R,5R,6R)-6-((E)3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-N-((3S,6R)-6-hydroxy-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl)-2-methoxy-acetamide (0.74 g, 1.4 mmol) is added and stirred for 16 h. The reaction is concentrated and chromatographed on silica (98% CH2Cl2/2% CH3OH) to give 0.3 g (28.8%) of tetradecanoic acid (3R,6S)-6-{(R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetylamino}-7-oxo-1-pyridin-3-ylmethyl-azepan-3-yl ester as a white solid. 1H NMR 300 MHz δ 8.54(s, 2H), 7.88 (d, 1H), 7.63 (d, 1H), 7.29 (m, 1H), 5.77 (d, 1H), 5.54(dd, 1H), 5.06 (d, 1H), 4.75 (m, 1H), 4.50 (m, 1H), 4.29 (m, 2H), 4.08 (d, 1H), 3.90 (d, 1H), 3.52 (s, 3H), 3.50 (m, 1H), 3.25 (d, 1H), 2.27 (t, 2H), 2.15 (m, 2H), 2.00 (m, 1H), 1.60 (m, 3H), 1.46 (d, 2H), 1.25 (m, 24H), 1.04 (s, 9H), 0.88 (t, 3H); MS (ESI) 730.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[Cl:19])=[CH:7][N:6]([CH2:20][C:21]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=2[F:31])[C:5]1=[O:32].C([O-])([O-])=O.[K+].[K+].Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48]>CN(C=O)C>[CH2:50]([O:49][C:47]([CH2:46][CH2:45][CH2:44][NH:1][C@H:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[Cl:19])=[CH:7][N:6]([CH2:20][C:21]2[C:26]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:24]=[CH:23][C:22]=2[F:31])[C:5]1=[O:32])=[O:48])[CH3:51]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cccc(-c2cn(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)CC(C)C)c2=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN[C@H](CC(C)C)Cn1c(=O)c(-c2cccc(OC)c2Cl)cn(Cc2c(F)cccc2C(F)(F)F)c1=O
Temperature: 95 °C

Procedure:
To a solution of compound 8b (25 mg, 0.048 mmol) in DMF (1 mL) was added K2CO3 (21 mg, 0.15 mmol) followed by ethyl 4-bromobutyrate (0.015 mL, 0.1 mmol). The mixture was heated at 95° C. for 16 hours, cooled to room temperature, and partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate/hexanes/triethylamine 500/500/5 to afford compound 8c. MS (CI) m/z 642.2, 644.2 (MH+).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:35][O:36][C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH:47]([CH:50]=O)[CH2:46][CH2:45]2)=[CH:41][CH:40]=[CH:39][N:38]=1>CN(C)C=O>[CH3:35][O:36][C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH:47](/[CH:50]=[CH:9]/[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH3:2])[CH2:46][CH2:45]2)=[CH:41][CH:40]=[CH:39][N:38]=1
Reactant: Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ncccc1CN1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ncccc1CN1CCC(/C=C/c2ccccc2C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
In N,N-dimethylformamide (10 ml) was suspended 1.15 g of [(2-methylphenyl)methyl]triphenylphosphonium bromide. To the suspension was added 288 mg of potassium tert-butoxide, followed by stirring for 15 minutes under ice-cooling. A solution of 500 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-piperidinecarboxaldehyde dissolved in 3 ml of N,N-dimethylformamide was added dropwise thereinto, followed by stirring at room temperature overnight. Ice-water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to give 473 mg of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].[C:28]([NH:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:28]([NH:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([NH:1][CH2:2][C:3]([N:5]([C:7]2[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]3)[CH3:6])=[O:4])=[O:41])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), (E)-3-(6-acetamidopyridin-3-yl)acrylic acid (56.1 mg) and N,N-dimethylformamide (2 ml) were added 1-hydroxybenzotriazole (43.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (56.9 mg) in a nitrogen stream at 0° C., and the resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was washed with an aqueous solution of saturated sodium hydrogencarbonate, water and brine successively, and dried over magnesium sulfate, and thereafter the solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography (methanol:dichloromethane=1:10, v/v), and solidified with diethyl ether and ethyl acetate to give 8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2methylquinoline (FR173657) (78.8 mg) as a grayish white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([S:25]([CH3:27])=[O:26])[CH:19]=1)[OH:17].C([BH3-])#N.[Na+]>CO>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]([NH:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([S:25]([CH3:27])=[O:26])[CH:19]=1)[OH:17])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCOCc1ccccc1
Reactant: CS(=O)c1cc(C(O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(CCOCc1ccccc1)NCC(O)c1ccc(O)c(S(C)=O)c1
Reaction time: 16 h

Procedure:
Combine 4-benzyloxy-2-butanone (1.78 g, 10 mmol) with 2-amino-1-(4-hydroxy-3-methylsulfinylphenyl)ethanol (10 mmol) in methanol (50 ml) and add sodium cyanoborohydride (0.63 g, 10 mmol). Let stand 16 hours, concentrate the solution and purify the crude product by chromatography on silica gel using chloroform: methanol: ammonium hydroxide (70:27:3) as eluent to obtain the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[CH:23]=[CH:22][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12].C(N(CC)CC)C.O>O1CCCC1>[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[CH:23]=[CH:22][C:16]2[CH2:17][CH2:18][N:19]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCCCCl)c1ccc2c(c1)CCNCC2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCc2ccc(C(=O)CCCCCl)cc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylsulfonyl chloride (804 μl) was added to a solution of 5-chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (2.4 g) obtained in Reference Example 121 and triethylamine (1.67 ml) in tetrahydrofuran (30 ml). After stirring at room temperature for 60 minutes, water (50 g) was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a pale yellow solid (2.2 g). Further recrystallization from ethanol-diethyl ether afforded the title compound as colorless crystals (1.92 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([C:46]([O:48][CH3:49])=[O:47])[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:57][C:54]1[CH:53]=[CH:52][C:51]([CH2:50][C:42]2([C:46]([O:48][CH3:49])=[O:47])[CH2:43][CH2:44][CH2:45][CH:40]([NH:39][C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=[C:8]4[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[O:19])[CH2:41]2)=[CH:56][CH:55]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: COC(=O)C1(Cc2ccc(F)cc2)CCCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(Cc2ccc(F)cc2)CCCC(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 85.2 %

Procedure:
In a flask, 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (567 mg, 1.15 mmol), methyl 3-amino-1-(4-fluorobenzyl)cyclohexanecarboxylate (1.09 mmol), and HATU (622 mg, 1.64 mmol) was dissolved in dimethylformamide (3 mL). The reaction mixture was stirred for 2 minutes at room temperature. Diisopropylethylamine (0.95 mL, 5.45 mmol) was added to the reaction. The reaction was allowed to stir for an additional 1 hr. Upon completion, the reaction was quenched with water (5 mL). The water layer was extracted with ethyl acetate (20 mL) three times. The organic fractions were combined, dried with sodium sulfate, and concentrated to yield the crude product. The crude compound was purified using flash chromatography (0-100% ethyl acetate in hexane gradient) to give the title compound (690 mg).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>C(O)C.O.[OH-].[Na+].O>[CH3:12][N:3]1[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]1[S:1][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([C:19](=[O:20])[C:18]2[CH:29]=[CH:30][C:15]([C:14]([F:13])([F:31])[F:32])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(C(F)(F)F)cc1
Reactant: Cn1c(S)nc2ccsc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(C(F)(F)F)cc3)cc2)nc2ccsc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.0 g) and 1N-sodium hydroxide/water (5.1 mg) in ethanol (10 ml) was added 4-(4-trifluoromethylbenzoyl)benzyl bromide (1.73 g) and the mixture was stirred at 60° C. for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate-hexane to provide the title compound as colorless solid (1.11 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O1CCCC1.C(N(CC)CC)C>C(OCC)(=O)C.[Cu].[I-]>[C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Fc1ccccc1Br
Reactant: C#CCCCCCCCCC
Agent: [Cu]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC#Cc1ccccc1F
Temperature: 55 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-bromofluorobenzene (17.5 g), 1-undecyne (18.3 g), tetrahydrofuran (50 ml), and triethylamine (70 ml) was added bistriphenylphosphine palladium(II)chloride (1.2 g) and copper(l) iodide (162 mg). The reaction mixture was stirred at 55° C. for 3 hr, and an additional 2-bromofluorobenzene (2.0 g) and bistriphenylphosphine palladium(II)chloride (200 mg) were added. The mixture was stirred at 55° C. overnight, allowed to cool to room temperature, diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled twice under vacuum to give 13.1 g (53%) of product.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.C(#N)C.[I:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>CCOCC>[I-:15].[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1)([OH:23])=[O:22]
Reactant: O=C(O)CCCCCI
Reactant: Cc1ccnc2ccccc12
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cc[n+](CCCCCC(=O)O)c2ccccc12
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a 250 mL flask were added lepidine (7.5 g, 52.4 mmol), acetonitrile (40 mL) and 6-iodohexanoic acid (14.0 g, 57.9 mmol). The mixture was heated at reflux under argon for 40 h and then was cooled to rt. The mixture was poured into stirred ether (700 mL) and the stirring was continued until the supernatant liquid was clear. The supernatant was decanted and the residue was dissolved in DCM (60 mL). The solution was poured slowly into stirred ether (700 mL). The initially formed oil solidified after stirring for approx. 3 h. The solid was crushed to a powder and stirring was continued for 1 h. The solid was filtered off, washed with ether (2×60 mL), and dried under vacuum to afford 14 as a tan colored solid (17.6 g, 87%).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([OH:18])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1.[C:19](O)(=[O:22])[CH:20]=[CH2:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:12]([O:18][C:19](=[O:22])[CH2:20][CH2:21][NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1
Reactant: OCC1CCCO1
Reactant: C=CC(=O)O
Reactant: Nc1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCNc1cccc2ccccc12)OCC1CCCO1
Temperature: 80 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
A coupling component for the preferred dye of this invention was prepared as follows: A mixture of 30 parts of 1-naphthylamine and 43 parts of tetrahydrofurfuryl alcohol was heated to 80°C. Glacial acrylic acid (16.5 parts) was then added dropwise over a 10 minute period at 80°-85°C. When the addition was complete, the mixture was heated to 90°-95°C. and held at that temperature for 17 hours. The reaction mixture was cooled to 30°C. p-Toluenesulfonic acid (12.5 parts) and toluene (40 parts) were then added and the mixture heated to 85°-95°C. to remove the toluene-water azeotrope. The mixture was cooled to 25°C., washed first with 10% aqueous sodium bicarbonate in order to remove the acidic catalyst, and then with water. The mixture was then heated with steam, distillation of the toluene-water azeotrope commencing at 85°C. The temperature gradually increased during the distillation until at 115°C., almost no distillate was apparent. The mixture was cooled to 85°C. and the lower organic layer was separated to yield 60.5 parts (73% yield) of tetrahydrofurfuryl-3-(1-naphthylamino)propionate having a purity of 76% when analyzed by vapor phase chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C(Br)C1C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)[NH2:5]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)[C@@H](N)CC1(Cc2ccccc2)C=CC=CC1

Procedure:
The synthesis of the benzylphenylalanine methyl ester is described in Scheme II-29. The imine is formed by treating phenylalanine methyl ester with benzaldehyde followed by deprotonation with lithium hexamethyldisilazide to generate the anion and alkylation with benzylbromide to give 1-benzylphenylalanine methyl ester 115. ##STR38##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[OH:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH:22]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[OH:23])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: O=C(NCC(O)c1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCC(O)c1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a solution of 6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.046 g, 0.092 mmol) in methanol (1 ml) was added 0.5M sodium methanolate in methanol (0.18 ml, 0.092 mmol), and the reaction was stirred at ambient temperature for 16 hours. It was concentrated, taken up in dichloromethane and hexanes, and concentrated again to yield 46 mg of the title compound (96% yield). MS (apci) m/z=501.8 (M-Na+2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:7]3=[O:23])=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2ccc(CNC(=O)Nc3ccc(Cl)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.47 g, 1.4 mmol) and triethylamine (0.27 mL, 2.0 mmol) in THF (8 mL) at 5˜10° C., was added 4-chlorophenyl isocyanate (0.28 g, 1.8 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (−1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (400 mg, 63% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min. kept 5 min, 6.18 min (98.9%); mp, 225-227° C.; 1HNMR (DMSO-d6) δ 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH), 4.41 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=6 Hz, 1H, CH2NH), 7.23-7.95 (m, 7H, Ar), 8.80 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.93, 23.38, 30.61, 42.33, 56.54, 119.23, 120.01, 123.67, 124.57, 126.53, 128.42, 133.95, 139.05, 139.37, 145.74, 154.53, 155.09, 160.46, 169.47, 172.60. LCMS MH=454, 456; Anal Calcd For C22H20N5O4Cl+0.8H2O: C, 56.43; H, 4.65; N, 14.95; Cl, 7.57. Found: C, 56.45; H, 4.56; N, 14.87; Cl, 7.69.
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])/[CH:5]=[CH:6]/[Sn](CCCC)(CCCC)CCCC)[CH3:2].[NH2:26][C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[N:30]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[C:28]=1I>CN(C)C=O.O>[NH2:26][C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[N:30]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[C:28]=1/[CH:6]=[CH:5]/[Si:4]([O:3][CH2:1][CH3:2])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1I
Reactant: CCCC[Sn](/C=C/[Si](OCC)(OCC)OCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCO[Si](/C=C/c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC)(OCC)OCC
Temperature: 90 °C
Reaction time: 120 h
Yield: 5.4 %

Procedure:
Tetrakis triphenylphosphine palladium(0) (160 mg, 0.14 mmol, 0.10 equiv) and (E)-triethoxy(2-(tributylstannyl)vinyl)silane (990 mg, 2.1 mmol, 1.5 equiv) were sequentially added to a stirred solution of methyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-iodopyrimidine-4-carboxylate (600 mg, 1.4 mmol, 1.0 equiv) in N,N-dimethylformamide (5.5 mL) at room temperature. The heterogeneous yellow mixture was heated at 90° C. and stirred for 5 d. The cooled reaction mixture was diluted with water (300 mL) and extracted with diethyl ether (3×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated under vacuum. The product was purified by acid free reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to provide the title compound as a yellow glass (38 mg, 6% yield): IR (thin film) 3315 (w), 3069 (w), 2974 (w), 1657 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=9, 8 Hz, 1H), 7.29 (d, J=18.5 Hz, 1H), 7.21 (dd, J=9, 2 Hz, 1H), 6.06 (d, J=18.5 Hz, 1H), 5.39 (br s, 2H), 3.98 (d, J=1 Hz, 3H), 3.92 (s, 3H), 3.89 (q, J=7 Hz, 6H), 1.26 (t, J=7 Hz, 9H); ESIMS m/z 500 [(M+H)+].