Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([O:6]C)=[O:5].O=C(CC1C=C(F)C(F)=CC=1F)CC(OC)=O.[OH-].[Na+]>CO.O>[NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(N)Cc1cc(F)c(F)cc1F
Agent: COC(=O)CC(=O)Cc1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(CC(=O)O)Cc1cc(F)c(F)cc1F

Procedure:
Methyl 3-amino-4-(2,4,5-trifluorophenyl)butanoate (5.8 g, 23.5 mmol), prepared from methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate according to the process of WO 10/122578, was refluxed in the solution of NaOH (1.88 g, 46.9 mmol) in MeOH (40 mL) and water (20 mL) overnight. After the completion of the reaction, the MeOH was evaporated and 80 mL of water was added. The pH of the solution was adjusted to 8 by addition of 6M HCl and the resulting white precipitate was filtered off and dried overnight in an oven at 100° C. to afford 3.5 g of (±)-Ia.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH:10]=1)[C:7]([NH:23][C:24]1([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCCC1c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A solution of 5-chloro-2-(2-phenylpyrrolidin-1-yl)nicotinic acid (D98) (150 mg, 0.5 mmol), methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (114 mg, 0.5 mmol) and N,N-Diisopropylethylamine (194 mg, 1.5 mmol) in dimethylformamide (10 ml) was stirred 1 h at room temperature, then benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (312 mg, 0.6 mmol) was added. The mixture was stirred at room temperature overnight, then poured into ice-water (20 ml) and extracted with ethyl acetate (2×20 ml). The organic solution was washed with brine (40 ml), dried over Na2SO4 and concentrated to obtain a residue which was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate (4:1). Collected fractions after solvent evaporation afforded the title compound (D142) (189 mg) as a yellow solid.
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)CCC>C1(C)C=CC=CC=1.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:2][C:1]([CH3:4])([CH3:3])[CH2:5][C:6]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:7]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A mixture of t-butylacetyl chloride (1 ml, 7.2 mmol), 2-(tributylstannyl)thiophene (2.4 ml, 7.56 mmol) and PdCl2(PPh3)2 (98 mg, 0.14 mmol) in toluene (50 ml) was heated at reflux until the starting material disappeared. After cooling at room temperature, the brown-black solution was diluted with ether and washed with a 0.1 N aqueous HCl solution. The organic phase was separated and stirred vigorously with a 10% w/v aqueous KF solution for 30 minutes. After filtration, the layers were separated and the organic one washed with water, brine, dried over MgSO4 and concentrated. The residual brown oil was chromatographied on silica gel (hexane/AcOEt 97/3) to give 3,3-dimethyl-1-(2-thienyl)-1-butanone 10 as a colorless oil (810 mg, 62%).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][CH:13]([NH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])C.[CH2:25](OC(OCC)OCC)[CH3:26].C(O)(=O)C>O>[Cl-:1].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH+:12]1[CH2:26][CH2:25][N:15]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:13]1
Reactant: Cl
Reactant: Cc1cc(C)c(NC(C)Nc2c(C)cc(C)cc2C)c(C)c1
Reactant: CCOC(OCC)OCC
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c(N2CC[NH+](c3c(C)cc(C)cc3C)C2)c(C)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A 500 mL three-neck round bottom flask, containing a Teflon-coated stirbar and fitted with an internal thermometer and a short path distillation head, was charged with bis-(2,4,6-trimethylphenylamino)ethane dihydrochloride (20.18 g, 54.63 mmol) and triethylorthoformate (200 mL). Acetic acid (98%, ca. 4 drops from a Pasteur pipette) was added, and the reaction vessel was placed in a 130° C. oil bath. As the beige slurry was heated and stirred, a water white liquid began to distill away from the reaction mixture which itself had taken on a pink tint. Heating was continued until distillation ceased, about 4 hours. The final temperature of the reaction mixture was 120° C. After the reaction mixture had cooled to ambient temperature, the pink color had discharged. The solid product was isolated by filtration and washed with hexanes (3×100 mL). Vacuum drying afforded 18.21 g (97%) of 1,3-Bis-(2,4,6-trimethylphenyl)imidazolinium chloride as a white, crystalline powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C@@H:9]1[C@H:13]([CH2:14]I)[CH2:12][CH2:11][N:10]1[C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C@@H:9]1[C@H:13]([CH2:14][N:1]=[N+:2]=[N-:3])[CH2:12][CH2:11][N:10]1[C@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])=[O:8]
Reactant: COC(=O)[C@@H]1[C@H](CI)CCN1[C@@H](C)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@H](CN=[N+]=[N-])CCN1[C@@H](C)c1ccccc1
Reaction time: 18 h

Procedure:
Sodium azide (5.34 mmol) was added to a solution of (2S,3R)-3-iodomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid methyl ester (Stage 36.5) (3.56 mmol) in DMF (30 mL) at rt. After 18 h, the reaction mixture was poured onto water and extracted with MTBE (2×). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep° silica gel column to to afford the title compound as a brown oil. HPLC: tR=3.26 min (method G); ESI-MS: [M+H]+ 289.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[NH:5][CH:6]=1.CN(C=O)C.CC(C)([O-])C.[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:6]=1
Reactant: O=C(O)c1cc(Cl)c[nH]1
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cn1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.2 %

Procedure:
To a mixture of 4-chloro-1H-pyrrole-2-carboxylic acid (0.20 g) and DMF (2.0 mL) was added potassium tert-butoxide (0.31 g) under ice-cooling, followed by stirring at room temperature for 15 minutes. To the reaction mixture was added 1-bromomethyl-4-chlorobenzene (0.29 g) under ice-cooling, followed by stirring at room temperature for 14 hours. To the reaction mixture was added water at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-chloro-1-(4-chlorobenzyl)-1H-pyrrole-2-carboxylic acid (0.06 g).
Reaction SMILES: CC1C(C)=CC=CC=1N.N1CCN=C1S(O)(=O)=O.[C:19]1([N:29]=[C:30]2[NH:34][CH2:33][CH2:32][NH:31]2)[C:28]2[CH2:27]CC[CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1>CC#N>[CH3:27][C:28]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:29]=[C:30]1[NH:31][CH2:32][CH2:33][NH:34]1
Reactant: c1cc2c(c(N=C3NCCN3)c1)CCCC2
Agent: Cc1cccc(N)c1C
Agent: O=S(=O)(O)C1=NCCN1
Solvent: CC#N
Product: Cc1cccc(N=C2NCCN2)c1C
Temperature: 155 °C
Yield: 17 %

Procedure:
2,3 Dimethylaniline (Aldrich, 236 mg, 1.95 mmol), imidazoline-2-sulfonic acid (292 mg, 1.95 mmol, (Compound 7 obtained as described above)) and CH3CN (4ml) were placed in a thick-walled glass tube and sealed with a TEFLON™ screw-cap. The reactants were heated to 155° C. for 6 hours The reaction was worked up as described for Compound 4 and chromatographed (SiO2 ; 70:30 CHCl3 /CH3OH saturated with NH3) to yield a light yellow oil which was recrystallized (hexane/isopropanol to yield 61 mg (17%) of the title compound as an off-white crystalline solid: mp 141°-144° C.; 1H NMR (300 MHz, CDCl3) & 6.98 (m, 1H); 6.80 (m, 2H), 5.31 (br, 2H); 3.42 (s, 4H); 2.31 (s, 3H); 2.12 (s, 3H); Mass spectrum m/e 189.1259 (C11H15N 3 requires 189.1266). Alternatively, and preferably alcohols, most preferably isobutanol, are used instead of CH3CN in this reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O>CN(C=O)C.O>[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:34][CH:33]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Reactant: BrCc1ccc(Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(Br)cc4)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[(2-hydroxyethyl)oxy]hexyl}-1,3-oxazolidin-2-one (2.00 g) in DMF (25 ml) under nitrogen was treated with sodium hydride (244 mg, 60% in oil) and the mixture was stirred at 20° for 15 min. 4-Bromobenzyl bromide (1.40 g) was added and the mixture was stirred at 20° for 18 h. Phosphate buffer solution (50 ml, pH6.5) and water (50mi) were added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (40 mm diameter column). Elution with EtOAc-PE (1:1) gave the title compound (2.125 g). LCMS RT=3.77 min.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17][C:16]([CH3:26])([CH3:25])[C:15]=4[CH:14]=3)[CH:11]=2)[CH:6]=[C:5]([C:27]([OH:29])=[O:28])[CH:4]=1.OC1C2C(=CC=C(C3C=CC4C(C)(C)CCC(C)(C)C=4C=3)C=2)C(C)=C(C(O)=O)C=1.CC1(C)C=CC(C)(C)C2C=C(C3C4CCCCC=4C=CC=3C(O)=O)C=CC1=2.CC1C2C(=CC(C3C=CC4C(C)(C)CCC(C)(C)C=4C=3)=CC=2)C=CC=1C(O)=O>>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:19]([CH3:23])([CH3:24])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:26])[C:15]=4[CH:14]=3)[CH:11]=2)[CH:6]=[C:5]([C:27]([OH:29])=[O:28])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cc12
Agent: CC1(C)C=CC(C)(C)c2cc(-c3c(C(=O)O)ccc4c3CCCC4)ccc21
Agent: Cc1c(C(=O)O)cc(O)c2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc12
Agent: Cc1c(C(=O)O)ccc2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc12
Product: CC1(C)CCC(C)(C)c2cc(-c3ccc4cc(C(=O)O)cc(O)c4c3)ccc21

Procedure:
4-methoxy-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphthoic acid; 4-acetoxy-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthyl)-2-methyl naphthoate; 4-acetoxy-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-methyl naphthoate; 4-hydroxy-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphthoic acid; 4-hydroxy-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8tetramethyl-2-naphthyl)-2-methyl naphthoate; 4-mercapto-1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-2-naphthoic acid; and 1-methyl-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphthoic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Br[CH2:12][C:13]1[CH:32]=[CH:31][C:16]2/[C:17](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:18]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=3[O:20][CH2:21][C:15]=2[CH:14]=1>>[C:28](/[C:27](=[C:17]1/[C:18]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=2[O:20][CH2:21][C:15]2[CH:14]=[C:13]([CH2:12][CH:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7])[CH:32]=[CH:31][C:16]/1=2)/[CH3:30])#[N:29]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: COCC(=O)CC(=O)OC
Product: COCC(=O)C(Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N)C(=O)OC
Yield: 82.7 %

Procedure:
[step 1] Using methyl 4-methoxy-3-oxobutanoate (816 mg, 5.58 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (1.0 g, 2.79 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 13G, step 1, (E)-methyl 2-{[11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl}-4-methoxy-3-oxobutanoate (977 mg, 83%) was obtained.
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[C:24]([Cl:39])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[F:60][CH:61]([F:78])[CH2:62][NH:63][CH:64]1[CH2:70][CH2:69][C:68]2=[C:71]([NH2:77])[C:72]([O:75][CH3:76])=[CH:73][CH:74]=[C:67]2[CH2:66][CH2:65]1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[N:26][C:21]([NH:77][C:71]2[C:68]3[CH2:69][CH2:70][CH:64]([NH:63][CH2:62][CH:61]([F:78])[F:60])[CH2:65][CH2:66][C:67]=3[CH:74]=[CH:73][C:72]=2[O:75][CH3:76])=[N:22][CH:23]=1
Reactant: COc1ccc2c(c1N)CCC(NCC(F)F)CC2
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1ccc2c(c1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCC(NCC(F)F)CC2

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with N*7*-(2,2-Difluoro-ethyl)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,7-diamine to afford 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]-N*4*-(2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine LC/MS (ESI): 540.27. 1H NMR (400 MHz, DMSO, d6) δ 8.99 (m, 2H), 8.71 (m, 1H), 8.31 (m, 1H), 7.79 (s, 2H), 7.14 (m, 2H), 7.04 (m, 2H), 6.88 (m, 2H), 6.61 (s, 1H), 6.38 (td, 1H), 3.78 (s, 3H), 3.65 (m, 2H), 3.38 (m, 2H), 3.04 (m, 1H), 2.84 (m, 1H), 2.71 (m, 1H), 2.29 (m, 2H), 1.34 (m, 2H).
Reaction SMILES: S([O:5][CH3:6])(OC)=O.C(=O)([O-])[O-].[K+].[K+].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>>[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:5][CH3:6])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COS(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(NC(C)=O)cc1
Temperature: 70 °C
Yield: 36.7 %

Procedure:
To a three-necked 100 ml flask equipped for reflux and fitted with a mechanical stirrer was added 10 ml (0.12 mol) of dimethyl sulfite, 2.0 g (0.014 mol) of potassium carbonate, and 5.0 g (0.033 mol) of p-acetamidophenol. The mixture was heated to 70° C. for six hours then quenched while hot with 50 ml of water. The solution was made basic with dilute caustic and the organic materials were extracted into methylene chloride. The extracts were concentrated in vacuo to give 2.0 g of p-acetamidoanisole.
Reaction SMILES: BrCC[Te](Br)(Br)[CH2:5][CH2:6][Br:7].O=O.[C:12]([O:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])(=[O:14])[CH3:13].[Br:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27].C(Br)C[Br:31].C=C.C(O)CO>C(O)(=O)C>[C:12]([O:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])(=[O:14])[CH3:13].[Br:22][CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27].[Br:31][CH:6]([Br:7])[CH3:5]
Reactant: BrCC[Te](Br)(Br)CCBr
Reactant: BrCCBr
Agent: C=C
Agent: CC(=O)OCCBr
Agent: O=O
Solvent: OCCO
Solvent: CC(=O)OCCOC(C)=O
Solvent: CC(=O)O
Product: CC(Br)Br
Reaction time: 1 h

Procedure:
1.05 g. (2.09 mmoles) of bis(2-bromoethyl)-tellurium dibromide, from Example 2, along with 4.0 g. glacial acetic acid (99.5 percent) was charged to a "Fisher-Porter" 35 ml. glass tube reactor equipped with a gas inlet and outlet tube, a pressure gauge and relief valve and a magnetic stirrer. The mixture was heated at a temperature of 150° C. under 16 psig oxygen with stirring for 1 hour. The reaction mixture was cooled and the products analyzed by gas liquid partition chromagraph (glpc.) showed 3.10 mmoles of ethylene glycol diacetate, 0.79 mmoles of 2-bromoethylacetate, 0.12 mmoles ethylene dibromide and a trace amount of ethylene. Based on stoichiometry that one mole of bis(2-bromoethyl)tellurium dibromide yields two moles of ethylene glycol precursors, i.e., ethylene glycol diacetate, 2-bromoethylacetate and dibromoethane, the mass balance was calculated to be 96 mole percent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=O)[O:10][C:8](=[O:9])[C:7]=12.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][C:18]=1[OH:24].[C:25]1([CH:32]=[CH:31][CH:30]=[C:28](O)[CH:27]=1)[OH:26]>>[Cl:16][C:17]1[C:18]([OH:24])=[CH:19][C:20]2[O:21][C:31]3[C:30](=[CH:28][CH:27]=[C:25]([OH:26])[CH:32]=3)[C:11]3([C:6]4[C:7](=[C:2]([Cl:1])[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]=4[Cl:13])[C:8](=[O:9])[O:10]3)[C:22]=2[CH:23]=1
Reactant: Oc1cccc(O)c1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Product: O=C1OC2(c3ccc(O)cc3Oc3cc(O)c(Cl)cc32)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Yield: 82.1 %

Procedure:
Treatment of tetrachlorophthalic anhydride (5 g, 17.48 mmol), 4-chlororesorcinol (2.78 g, 19.23 mmol) and resorcinol (2.12 g, 19.23 mmol) according to the procedure described in Example 1 Step 1 provided 7.24 g of 18.6% pure 2′,4,5,6,7-pentachloro-3′,6′-dihydroxy-3H-spiro[isobenzofuran-1,9′-xanthen]-3-one that was collected and taken to the next step as a mixture.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[S:20]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21].N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:39]/[C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:22])=[O:21])[CH:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Reactant: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C)CC4)C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.525 g, 2.00 mol) in methanol (10 mL) was added with 1-tosyl-1H-indole-3-carboxaldehyde (0.599 g, 2.00 mmol) and piperidine (0.017 g, 0.200 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol, and the solid was suspended in methanol and thereby washed to obtain the objective (Z)-6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]-2-[(1-tosyl-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (0.887 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.S(Cl)([Cl:19])(=O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[Cl:19][C:7]1[C:6](=[O:8])[N:5]2[CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[S:11][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1cn2c(=O)cc(C)nc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cn2c(=O)c(Cl)c(C)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (5.5 g; m.p. 146°-148° C.), prepared according to Example 1, was reacted with sulfuryl chloride (3.6 g) in dichloroethane (150 ml) under stirring at room temperature for 30 minutes. The reaction mixture was poured into ice water containing NaHCO3 : the organic phase was separated and evaporated in vacuo to dryness: crystallization from methanol gave 6-chloro-7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (4.28 g), m.p. 218°-220° C., which was reacted with benzaldehyde (3.5 g) in methanol (150 ml) in the presence of sodium methoxide (2.68 g) under stirring at reflux temperature for 24 hours. The precipitate was filtered and dissolved in a mixture of dimethylformamide and formic acid; the solution was diluted with ice water and the precipitate was filtered and washed with water until neutral. Crystallization from CH2Cl2 -methanol gave 3.1 g of 6 -chloro-7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, m.p. 265°-270° C. dec., N.M.R. (CF3COOD-CDCl3) δp.p.m.: 7.59 (d) (1H,β-ethenyl proton), 7.40-7.80 (m) (5H, phenyl protons), 8.01 (d) (1H,α-ethenyl proton), 8.88 (s) (1H, C-3 proton); JHαHβ =16 Hz.
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([Cl:19])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Cl

Procedure:
(S)-2-Acetylthiomethyl-3-phenylpropanoic acid (Ia S) (Example 2, stage e) is treated with thionyl chloride according to the same procedure as that described in Example 3, stage f.
Reaction SMILES: [C:1]([O:14][CH:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:16][C:17]([O:19]C(C)(C)C)=O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:35][CH2:36][C:37]([NH:39][C@H:40]([C:43]([OH:45])=[O:44])[CH2:41][OH:42])=[O:38]>>[C:1]([O:14][CH:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:16][C:17]([NH:35][CH2:36][C:37]([NH:39][C@H:40]([C:43]([OH:45])=[O:44])[CH2:41][OH:42])=[O:38])=[O:19])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC(CCCCCCCCCCC)CC(=O)OC(C)(C)C
Reactant: NCC(=O)N[C@@H](CO)C(=O)O
Product: CCCCCCCCCCCC(=O)OC(CCCCCCCCCCC)CC(=O)NCC(=O)N[C@@H](CO)C(=O)O
Yield: 61.5 %

Procedure:
Starting from tert-butyl 3-dodecanoyloxytetradecanoate (165 mg) prepared by the method described in Preparation 3-(2) and N-glycyl-L-serine (162 mg), N-[N-(3-dodecanoyloxytetradecanoyl)glycyl]-L-serine (120 mg) was obtained as an amorphous powder according to similar manner to that of Example 1.