Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH2:20]([O-:22])[CH3:21].[Na+]>O>[CH2:20]([O:22][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1)[CH3:21]
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1cc(-c2ccccn2)nc(-c2ccccn2)c1

Procedure:
In a nitrogen atmosphere, 900 mg (3.4 mmol) of 4′-chloro-[2,2′;6′,2″]terpyridine are added to 15 ml of a 0.7M ethanolic sodium ethanolate solution. The mixture is heated at reflux for 20 hours. The mixture is allowed to cool and 20 ml of water are added, and 4′-ethoxy-[2,2′;6′,2″]terpyridine is filtered off in the form of a white solid. 1H-NMR (360 MHz, DMSO-d6): 1.40 (t, 3H, 6.8 Hz); 4.28 (q, 2H, 6.8 Hz); 7.42-7.53 (m, 2H); 7.93 (s, 2H); 7.95-8.02 (m, 2H); 8.58 (d, 2H, J=8.1 Hz); 8.69 (d, 2H, J=4 Hz).
Reaction SMILES: CC([O-])(C)C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[C:28]([CH:31]=1)[C:29]#[N:30]>CS(C)=O.ClCCl>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[O:15])=[CH:12][CH:13]=2)=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Reactant: N#Cc1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN1CCN(C(=O)c2ccc(Nc3ccc(Br)cc3C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.8 %

Procedure:
KOtBu (2.81 g, 25.08 mmol) was dissolved in 20 ml DMSO in a round bottom flask. (4-aminophenyl)(4-methylpiperazin-1-yl)methanone (5.0 g, 22.80 mmol) in 30 ml DMSO was added and the resulting mixture was stirred for 15 minutes at r.t. The mixture was cooled in an iced bath for 5 minutes. 5-bromo-2-fluorobenzonitrile (4.6 g, 23.00 mmol) in 20 ml DMSO was added. The ice bath was removed and the mixture stirred for 5 hours while warming to room temperature. Additional KOtBu (2 g, 17.82 mmol) was added and the mixture stirred at room temperature overnight. The mixture was diluted with dichloromethane, extracted twice with water, once with brine, then dried over MgSO4, filtered and concentrated. 8.8 g crude brown oil were isolated. The crude product was recrystallized from dichloromethane+ethyl acetate+hexanes. 5.012 g pale yellow crystals were collected by filtration. The mother liquor was concentrated and purified by chromatography on silica, using a gradient from 100% Solvent A to 50% Solvent A+50% Solvent B. Solvent A: 99% dichloromethane+1% Triethylamine, Solvent B: 99% Ethylacetate+1% Triethylamine. Evaporation of product containing fractions gave additional 1.8 g product of ˜70% purity. MS (ESI) m/z 399/401(M+H). 1H NMR (CDCl3) δ ppm 7.63 (s, 1H), 7.48 (d, 1H, J=9.2), 7.42 (d, 2H, J=7.9), 7.18-7.14 (m, 3H), 6.41 (s, 1H), 3.80-3.40 (bm, 4H), 2.42 (bs, 4H), 2.32 (s, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].Br[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(N(CC)C(C)C)(C)C>>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:32]5[N:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Reactant: Brc1ncccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(c5ncccn5)C4)c3C2)cc1C(F)(F)F
Temperature: 160 °C
Yield: 22.4 %

Procedure:
To a glass vial was added 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (prepared using step 1 of example 91 from intermediate 13) (75 mg, 0.16 mmol), 2-bromopyrimidine (55 mg, 0.342 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.85 mmol). The vial was capped and the mixture heated in the microwave at 160° C. for 20 min. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-1-pyrimidin-2-yl-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a brown solid (17 mg, 21% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.23-2.43 (m, 2 H) 2.85-2.99 (t, 2 H) 3.22-3.94 (m, 9 H) 4.08-4.27 (m, 2 H) 5.70-5.80 (m, 1 H) 6.56-6.66 (t, 1 H) 7.76-7.87 (m, 1 H) 8.12-8.27 (m, 1 H) 8.28-8.42 (m, 2 H) 8.59-8.68 (m, 1 H) LCMS: [M+H]+=474.2, Rt(1)=1.91 min.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15]C(CCCCC3C=CC=CC=3)CC(NO)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].CO>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([SH:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)NO)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 138.4 %

Procedure:
A suspension of 3,3′-dicyclopentyloxy-4,4′-dimethoxyphenyldisulfide (15 g, Reference Example 3) and sodium borohydride (3.18 g) in anhydrous tetrahydrofuran (150 ml) at reflux was treated dropwise with anhydrous methanol (15 ml) over 1 hour. The cloudy yellow solution was stirred at reflux for 30 minutes then cooled to room temperature and stirring was continued for 18 hours. The reaction mixture was partitioned between hydrochloric acid (400 ml, 1N) and diethyl ether (400 ml). The aqueous layer was extracted three times with diethyl ether (200 ml). The combined organic phases were washed with hydrochloric acid (100 ml), then with water (100 ml) and then extracted three times with sodium hydroxide solution (200 ml, 0.2N) and once with water (200 ml). The combined aqueous extracts were acidified by addition of hydrochloric acid (1N) and then extracted five times with diethyl ether (200 ml). The combined ether extracts were washed with water (200 ml) then with brine (200 ml), then dried over magnesium sulphate and then evaporated to give the title compound (10.5 g) as a pale yellow oil. NMR (CDCl3): δ1.60 (m,2H), 1.80-2.00 (m,6H), 3.40 (s,1H), 3.80 (s,3H), 4.73 (m,1 H), 6.74 (d,1H), 6.88 (dd,2H). Mass spectrum (FAB): m/z 224 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[O:9]=[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]1[CH:20]([CH2:24][CH3:25])C(O)=O.FC(F)(F)C(O)=O.N>O.[N+]([O-])([O-])=O.[Ag+].C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH:20]([N:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]1=[O:9])[CH2:24][CH3:25]
Reactant: CCC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: Clc1ccc(Cl)nn1
Agent: [Ag+]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(c1cc(Cl)nnc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
3,6-Dichloropyridazine (596 mg, 4 mmol), 2-(1,3-dioxoisoindolin-2-yl)butanoic acid (1.59 g, 6.8 mmol), silver nitrate (67.9 mg, 0.4 mmol), trifluoroacetic acid (91.2 mg, 0.8 mmol) and water (10 mL) were heated at 70° C. with stirring, and to the resulting mixture, diammonium peroxodisulfate (1.64 g, 7.2 mmol) in water (2 mL) was added dropwise over 30 minutes. After the dropwise addition, the resulting reaction mixture was stirred at 70° C. for 30 minutes, then mixed with 10 mL of ethyl acetate and allowed to cool to room temperature. The reaction mixture was cooled with ice, then basified with 28% aqueous ammonia (to pH 9) and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate=1/1) to give a crude product, which was used for the next reaction.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1ccccn1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccccn1)O2

Procedure:
This compound was prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-bromopyridine as described in Example 14. The compound was isolated by chromatography as in Example 14 and was crystallized from ethyl acetate to give colorless crystals with m.p. 179°-181° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[NH:11][C:12]1[N:16]([CH3:17])[C:15]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]3)[C:20]([Cl:22])=[CH:21][C:14]=2[N:13]=1.[F:35][C:36]([F:43])([F:42])[CH:37]([CH3:41])[C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:38](=[O:39])[CH:37]([CH3:41])[C:36]([F:43])([F:42])[F:35])=[CH:5][C:4]=1[NH:11][C:12]1[N:16]([CH3:17])[C:15]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([F:31])([F:32])[F:30])[CH2:25][CH2:24]3)[C:20]([Cl:22])=[CH:21][C:14]=2[N:13]=1
Reactant: CC(C(=O)O)C(F)(F)F
Reactant: Cn1c(Nc2cc(CN)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1ccc(C(F)(F)F)c(Nc2nc3cc(Cl)c(N4CCC(C(F)(F)F)CC4)cc3n2C)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to the procedure in Example 94, step (c) using 4-trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine (110 mg; 0.22 mmol), 3,3,3-trifluoro-2-methylpropanoic acid (31 mg; 0.22 mmol), HBTU (83 mg; 0.22 mmol), TEA (45 mg; 0.44 mmol), DMF (2 mL).
Reaction SMILES: Br[C:2]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[CH2:11]([C:2]1([CH:22]2[CH2:23][NH:24][CH2:25][CH2:26][N:21]2[CH2:20][CH2:19][OH:18])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCN1CCNCC1
Reactant: O=C1NC(=O)C(Br)(Cc2ccccc2)C(=O)N1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(Cc2ccccc2)(C2CNCCN2CCO)C(=O)N1
Temperature: 25 °C

Procedure:
A solution of 5-Bromo-5-benzylbarbituric Acid (2.15 g) and N-(2-hydroxyethyl)piperazine in 50 ml of ethanol is refluxed for 4 hours, then it is cooled to room temperature and added with 4 ml of triethylamine. The solvent is evaporated off and the white residue is redissolved in a ethyl acetate/methanol 3:1 mixture. An ornage solid crystallizes, which is recovered by filtration. After recrystallization from ethanol 0.62 g of the product are obtained, m.p. 243-246° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[S:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:10][C:9]=2[CH:8]=[CH:7]1.[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:12]1[C:13]2[S:6][CH:7]=[CH:8][C:9]=2[NH:10][C:11]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:3]
Reactant: COC(=O)c1cc2sccc2[nH]1
Reactant: C=O
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1[nH]c2ccsc2c1CN(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
Under N2, to 9 mL of glacial acetic acid were added N,N-dimethylamine (40% aqueous solution) (437 mg, 9.94 mmol), formaldehyde (37% aqueous solution) (283 mg, 9.90 mmol), and methyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (1.8 g, 9.94 mmol). The temperature was kept between 0-5° C. while the components were added. The reaction mixture was heated at reflux for 1 h, and then allowed to stand at rt for 12 h. The mixture was poured onto 30 g of ice, and was brought to pH 10 by careful addition of 10% sodium hydroxide. The temperature was not allowed to exceed 10° C. while the base was added. The gummy substance that precipitated solidified when stored in the refrigerator overnight. The solid was collected and dried in a vacuum. It was recrystallized from petroleum ether (30-60° C.) to yield methyl 6-[(dimethylamino)methyl]-4H-thieno[3,2-b]pyrrole-5-carboxylate (1.65 g, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 2.36 (s, 6H) 3.86 (s, 3H) 3.89 (s, 2H) 6.85 (d, J=5.32 Hz, 1H) 7.28 (d, J=5.32 Hz, 1H) 9.84 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11](C3SC=CC=3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O)(=O)=O.C[C:26]1(C)[O:30][CH:29]([CH2:31]O)CO1.O>CN(C)C=O>[NH:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:31][CH:29]2[O:30][CH2:26]2)=[CH:7][CH:6]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(p-hydroxyphenyl)-4-(2-thienyl)imidazole (19.5 g, 0.08 m) in dimethylformamide (65 ml) is added to a stirred suspension of sodium hydride (4.8 g, 0.10 m, 50% dispersion in mineral oil) in dimethylformamide (20 ml) at 80° C. After stirring at 80° C. for 0.5 hours, a solution of 2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane methanesulfonate, (I) (16.82 g, 0.08 m) in dimethylformamide (20 ml) is added rapidly and the mixture is stirred under nitrogen at 80° C. for 17 hours. The reaction mixture is poured into H2O (400 ml) and extracted with ether (3×350 ml). The combined extracts are washed with 5% NaOH solution (2×250 ml) and with H2O (3X), dried, and the solvent is evaporated under reduced pressure to yield crude (II) (14.22 g) which is used without further purification.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].[Br:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1>C(Cl)(Cl)Cl>[BrH:5].[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[CH2:6][S:3][C:1](=[NH:4])[CH3:2]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(N)=S
Solvent: ClC(Cl)Cl
Product: Br
Product: CC(=N)SCc1ccc2ccccc2c1
Yield: 78.6 %

Procedure:
Thioacetamide (326.0 mg, 4.339 mmol) and 2-bromomethyl-naphthalene (959.0 mg, 4.337 mmol) were placed in a 50 mL round-bottom flask. 20 mL of CHCl3 were added and the mixure was refluxed for 3 h at which time a white precipitate formed. The mixture was cooled and the precipitate collected. The precipitate was washed with 20 mL of CH2Cl2 and placed under vacuum for drying to give 1.01 g of thioacetimidic acid naphthalen-2-ylmethyl ester hydrobromide salt as a fine white powder.
Reaction SMILES: [OH-].[K+].C([OH:7])(C)(C)C.[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([C:18]#[N:19])=[N:16][OH:17].Cl>O>[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](=[N:16][OH:17])[C:18]([NH2:19])=[O:7]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Reactant: CC(C)(C)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C)c(OCc2ccccc2C(=NO)C(N)=O)c1
Yield: 60 %

Procedure:
85% Potassium hydroxide (6.12 g, 92.8 mmol) and tert-butyl alcohol (15 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-hydroxyiminobenzyl cyanide(E/Z=15/85)(1.30 g, 4.64 mmol). The mixture was heated under reflux for 5 hours. After completion of the reaction, the reaction mixture was neutralized with 6N hydrochloric acid, and water (100 ml) was added. The resulting mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from n-hexane/ethyl acetate to give 2-[2-(2,5dimethylphenoxymethyl)phenyl]-2-hydroxyiminoacetamide (0.83 g, Yield: 60.0%, Z=at least 98%) as colorless crystals.
Reaction SMILES: C1(C)C=CC=C(C(O)=O)C=1.S(=O)(=O)(O)O.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1)=[O:19].[Br:27]N1C(=O)CCC1=O>CO>[CH3:16][O:17][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][Br:27])[CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1
Agent: Cc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc(CBr)c1

Procedure:
This is prepared as follows: 3-Toluic acid is converted with methanol in the presence of sulfuric acid into 3-toluic acid methyl ester, which reacts with N-bromosuccinimide to give 3-bromomethyl-benzoic acid methyl ester. Reaction of bromomethyl-benzoic acid methyl ester with triphenylphosphane finally leads to 3-(benzoic acid methyl ester)-methyltriphenylphosphonium bromide.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:20]([CH2:23]C1C=CC(OC2C=CC=CC=2C(O)=O)=CC=1)(O)=O>C(O)C>[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:23])=[O:18])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)Cc1ccc2oc3ccccc3c(=O)c2c1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2C(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc2oc3ccccc3c(=O)c2c1

Procedure:
9-Oxo-9H-xanthene-2-acetic acid, melting point 226°-228° C., is prepared from 2-(4-carboxymethylphenoxy)benzoic acid (Example 10f) analogously to Example 10c and is reacted with ethanol to give ethyl 9-oxo-9H-xanthene-2-acetate, melting point 97°-98° C.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15]1[C:29]([O:30][CH3:31])=[CH:28][C:18]2[CH2:19][C@@H:20]([C:25]([OH:27])=O)[S:21][CH2:22][C:23](=[O:24])[C:17]=2[CH:16]=1.[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O.O>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25]([C@@H:20]2[CH2:19][C:18]3[CH:28]=[C:29]([O:30][CH3:31])[C:15]([O:14][CH3:13])=[CH:16][C:17]=3[C:23](=[O:24])[CH2:22][S:21]2)=[O:27])=[CH:47][CH:46]=1)([O:39][CH2:40][CH3:41])=[O:45])[CH3:44]
Reactant: COc1cc2c(cc1OC)C(=O)CS[C@H](C(=O)O)C2
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@@H]2Cc3cc(OC)c(OC)cc3C(=O)CS2)cc1)OCC
Temperature: 0 °C
Reaction time: 15 h
Yield: 40.2 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.228 g) in dichloromethane (5 ml) was added to a solution of (S)-(+)-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.28 g) and diethyl 4-aminobenzylphosphonate (0.241 g) in N,N-dimethylformamide (DMF) (5 ml) at 0° C., followed by the addition of 1-hydroxybenzotriazole (HOBt) (0.167 g). This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off; the residue was treated with ethanol-isopropyl ether and the solid was removed by filtration. The filtrate was concentrated and the residual oil was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-chloroform-methanol (15:15:1, v/v), (2S)-(+)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-7,8-dimethoxy-5-oxo-3-benzothiepin-2-carboxamide (0.202 g, 40%) was obtained. Colorless amorphous solid. Melting point 97-99° C. Optical rotation [α]D (23° C.) +155.3° (c=0.50, CHCl3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(C1[O:22]C1)Cl.C(O)(C)C.[OH-].[Na+]>O>[OH:1][C:2]1([OH:22])[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH2:3]1
Reactant: ClCC1CO1
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=Cc1ccccc1)C1=CCC(O)(O)C=C1
Temperature: 55 °C

Procedure:
4,4'-Dihydroxy-alpha-methylstilbene 152.73 grams, 1.35 hydroxyl equivalents) from A above, epichlorohydrin (624.58 grams, 6.75 moles), deionized water (54.31 grams, 8.0 percent by weight of the epichlorohyrin used) and isopropanol (336.31 grams, 35 percent by weight of the epichlorohydrin used) is added to a reactor and heated to 55° C. with stirring under a nitrogen atmosphere. Once the 55° C. reaction temperature is achieved, sodium hydroxide (48.6 grams, 1.22 moles) dissolves in deionized water (194.4 grams) is added dropwise to the reactor over a 45 minute period so as to maintain reaction temperature between 55° and 59° C. Ten minutes after completion of the aqueous sodium hydroxide addition, the stirring is stopped and the aqueous layer which separated from the reaction mixture is pipetted off and discarded. Stirring is resumed and after a total of twenty minutes following completion of the initial aqueous sodium hydroxide addition, a second solution of sodium hydroxide (21.6 grams, 0.54 mole) dissolved in deionized water (86.4 grams) is added to the reactor over a twenty minute period 30 as to maintain the 55° C. reaction temperature. Fifteen minutes after completion of the aqueous sodium hydroxide addition, the recovered reaction mixture is added to a separatory funnel and washed with 750 milliliters of deionized water. The separated organic layer is washed a second time (750 milliliters deionized water), recovered and then rotary evaporated under vacuum for 45 minutes at 110° C. then 30 minutes at 130° C. The product is recovered (218.6 grams) as a crystalline solid with an epoxide equivalent weight of 183.33.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].CN(C)C=O>O>[O:23]=[C:21]1[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](=[O:28])[N:22]1[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOP(=O)(Cc1ccccc1CBr)OCC
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccccc1CN1C(=O)c2ccccc2C1=O)OCC
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.1 %

Procedure:
A mixture of diethyl [2-(bromomethyl)benzyl]phosphonate (11.2 g), potassium phthalimide (6.46 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was ashed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave diethyl {2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzyl}phosphonate (11.3 g, 83%) as colorless prism crystals. melting point: 91-92° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][CH2:31][CH2:32][OH:33]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([NH:30][CH2:31][CH2:32][OH:33])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)NCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-(methyl)-propionic acid (1 g) in tetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole (889 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2-aminoethanol (0.38 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 2-[2-benzyloxycarbonylamino-2-(methyl)propionylamino]ethanol (973 mg).