Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][C:41]([O:47][CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])=[CH:42][CH:43]=2)[CH:38]=1.[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][C:41]([O:47][CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:53])([CH3:55])[CH3:54])=[CH:42][CH:43]=3)[CH:38]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[Si](C)(C)CCOCOc1ccc2ccc(CCl)cc2c1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3ccc(OCOCC[Si](C)(C)C)cc3c2)cc1

Procedure:
reacting the product of step c) with 2-chloromethyl-7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene and sodium hydride to form (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylic acid tert-butylester;
Reaction SMILES: C([N:8]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])C1C=CC=CC=1>[Pd].C(O)C>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(C(=O)OCC)N(Cc1ccccc1)Cc1ccc(OC)cc1OC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NCc1ccc(OC)cc1OC)C(=O)OCC
Yield: 97 %

Procedure:
61.7 g. (0.149 moles) of diethyl N-benzyl-N-(2,4-dimethoxybenzyl)-amino-malonate prepared according to Example 7(b) are hydrogenated in the presence of 20 g. of palladium-on-charcoal, in 500 ml. of ethanol, under atmospheric pressure. The catalyst is filtered off and the filtrate is evaporated. 47.1 g. (97%) of diethyl N-(2,4-dimethoxybenzyl)-amino-malonate are obtained. If desired, the product is converted into the corresponding hydrochloride, which melts at 122° to 124° C. (EtOAc).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11]([N:14]([O:16][CH3:17])[CH3:15])(=[O:13])=[O:12])[S:10][C:3]=12.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28].C([O-])([O-])=O.[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11]([N:14]([O:16][CH3:17])[CH3:15])(=[O:13])=[O:12])[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CON(C)S(=O)(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CON(C)S(=O)(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 82 (400 mg, 1.37 mmol), 2-fluoro-4-nitrophenol (321 mg, 2.05 mmol) and K2CO3 (756 mg, 5.48 mmol) were heated to 190° C. in diphenyl ether (55 ml) for 3 hrs. The mixture was cooled to room temperature, diluted with DCM and filtered. The filtrate was concentrated and purified by column chromatography (eluent EtOAc:hexane, 1:1) to afford title compound 83 (225 mg, 40% yield). MS (m/z) 414.0 (M+H).
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:12][CH2:11][C:10]([OH:14])=[O:13])=[O:9])[CH3:2]
Reactant: C=CC(=O)O
Reactant: CCCCOP([O-])CC
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCC(=O)O
Yield: 90.5 %

Procedure:
149 g (1 mol) of butyl ethylphosphonite (produced as in Example 2) and 86 g (1.2 mol) of acrylic acid in 217 g of toluene are heated to about 100° C. While stirring, 124 g of a 10% strength solution of WakoV65 in toluene are metered in. The solvent is distilled off in vacuo to leave 201 g (91% of theory) of 3-(ethylbutoxyphosphinyl)propionic acid.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:27]([NH2:28])=[CH:26][C:9]2[CH2:10][C@@H:11]3[C:16]([CH3:18])([CH3:17])[C@:15]([CH3:19])([C:8]=2[CH:7]=1)[CH2:14][CH2:13][N:12]3[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22].C(O)(=O)C>O>[F:23][C:21]([F:24])([F:22])[C:20]([N:12]1[CH2:13][CH2:14][C@:15]2([CH3:19])[C:16]([CH3:17])([CH3:18])[C@H:11]1[CH2:10][C:9]1[CH:26]=[C:27]3[N:28]=[N:1][NH:5][C:6]3=[CH:7][C:8]=12)=[O:25]
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)[C@H]2Cc3cc4nn[nH]c4cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaNO2 (330 mg) in water (2 mL) is slowly added to a flask charged with a stir bar, 1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (650 mg), and acetic acid (15 mL) and chilled in an ice bath. The resulting mixture is stirred in the cooling bath for 2 h and at ambient temperature for 1 h. Then, the solution is poured into ice-cold water and the precipitate formed is separated by filtration and dried to afford the title compound that is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[N:14][O:15][C:16]=2/[CH:17]=C/C2C=CC=CC=2)=[N:6][CH:5]=1.I([O-])(=O)(=O)=[O:34].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:34])=[N:6][CH:5]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2/C=C/c2ccccc2)nc1
Agent: O=[Os](=O)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C=O)nc1
Temperature: 120 °C
Yield: 64.8 %

Procedure:
6-[3-(4-Chloro-phenyl)-5-([E]-styryl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (6.35 g, 14.2 mmol) was treated with osmium(VIII) oxide (90.3 mg, 355 μmol), sodium metaperiodate (12.2 g, 56.8 mmol) and benzyltriethylammonium chloride (1.32 mg, 5.68 mmol) in dioxane (140 mL) and water (47 mL). The mixture was heated for 35 min at 120° C. in a microwave. Extraction with ethyl acetate/water and chromatogaphy (silica, ethyl acetate:heptane 1:9 to 1:1) afforded the title compound (3.43 g, 65%) as a white solid. MS: m/e=373.1 [M+H]+.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][NH:7]1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[C:15]([F:22])[CH:14]=1>CCCCCC.CCOCC>[C:1]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][N:7]1[C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=1[F:22])=[O:21])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1CSCCN1
Reactant: O=C=Nc1ccc(Cl)cc1F
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)C1CSCCN1C(=O)Nc1ccc(Cl)cc1F
Yield: 87.7 %

Procedure:
An emulsion of 14 g of 3-carbethoxythiomorpholine in 50 ml of n-hexane was added dropwise to a solution of 14 g of 4-chloro-2-fluorophenylisocyanate in 60 ml of anhydrous ether at 15° to 28° C. with stirring. A heavy oil formed after the addition. The oil crystallized after stirring at room temperature for 15 min. The precipitate was collected by filtration to give 24.3 g of 3-carbethoxy-4-(4-chloro-2-fluorophenylaminocarbonyl)thiomorpholine, m.p. 111.5°-112.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:32]([N:34]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[Cl-].C[NH3+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([CH2:28][O:29][CH3:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH:34][CH3:32])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCc1ccc(Oc2cc(OC)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: C[NH3+]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (270 mg), 1-hydroxybenzotriazole monohydrate (216 mg), methylammonium chloride (95 mg), triethylamine (0.2 mL) and N,N-dimethylformamide (13 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100 to 5/95, volume ratio), followed by silica gel column chromatography (methanol/ethyl acetate=0/100 to 8/92, volume ratio) to give a yellow oil. The oil was crystallized from acetonitrile-diethyl ether to give white crystals. The crystals were recrystallized from acetonitrile-diethyl ether to give the title compound (204 mg, 66%) as colorless crystals. MS 441 (MH+). mp 102-104° C.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C(O[C:44](=[O:62])[CH:45]=[C:46]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=1)CCC>CCCCCC>[Br:61][C:58]1[CH:59]=[C:60]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:46]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=1)[CH:45]=[C:44]2[OH:62]
Reactant: CCCCOC(=O)C=C(Nc1ccc(Br)cc1)c1cccc(F)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Temperature: 250 °C
Reaction time: 1 h

Procedure:
Dowtherm A (a eutectic mixture of 26.5% diphenyl and 73.5% diphenyl oxide) (1.2 L) was charged into a round-bottom flask equipped with a condenser, magnetic stirrer, thermocouple, heating mantle with a variable voltage controller, and a nitrogen inlet, and heated to 250° C. To this was cautiously added in small portions 48 g (0.11 moles) of 3-(4-bromophenylamino)-3-(3-fluorophenyl)-acrylic acid butyl ester. As portions were added gas was evolved and foaming occurred. Crystals of product began to form and adhere to the sides. After all the material had been added the heating of the reaction was continued for 1 hour. The mixture was then cooled to room temperature and hexane was added. A solid product was collected by vacuum filtration and washed with hexane. After drying in a vacuum oven, 35.7 g (90%) of product was recovered.
Reaction SMILES: Br[C:2](Br)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1.C(=O)(O)[O-:23].[Na+].[Cl-].[Na+]>O1CCCC1.O.[N+]([O-])([O-])=O.[Ag+]>[O:23]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1
Reactant: O=C([O-])O
Reactant: BrC(Br)(c1ccccn1)c1nsc2nc3ccccc3n12
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccccn1)c1nsc2nc3ccccc3n12
Reaction time: 48 h
Yield: 78 %

Procedure:
To a solution of 3-[dibromo(2-pyridyl)methyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole (2.02 g, 4.76 mmol) in 75 mL tetrahydrofuran was added a solution of silver nitrate (0.890 g, 5.24 mmol) in 75 mL water. The suspension was stirred for 2 days and then basified to pH 6 with aqueous sodium bicarbonate. After the addition of 1 mL saturated aqueous sodium chloride, the mixture was filtered on celite and the celite was washed with ethyl acetate. After extraction with water, the ethyl acetate was dried and evaporated to give a crude residue which was purified by flash chromatography using a mixture of chloroform/methanol 10:0.1 as the eluent. 1.05 g (78%) of the title compound was obtained as a yellow solid: mp 182-186° C. (dec); 1H NMR (CDCl3)δ 8.85 (m, 1H), 8.31 (dt, 1H), 8.19 (d, 1H), 8.01 (td, 1H), 7.83 (d, 1H), 7.63 (ddd, 1H), 7.50 (ddd, 1H), 7.35 (ddd, 1H) ppm; IR (film) 1673, 1511, 1444, 1235, 1057, 879, 733 cm-1 ; MS m/z 280 (M+), 148 (M+ -(2-pyridyl)C(O)CN).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:43])([F:42])[C:23]1[CH:24]=[C:25]([C@@H:33](OC(=N)C(Cl)(Cl)Cl)[CH3:34])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1>>[F:21][C:22]([F:42])([F:43])[C:23]1[CH:24]=[C:25]([C@H:33]([O:20][C@@H:10]2[C@@H:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH3:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccc(F)cc2)[C@@H](O)C1
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@@H](O[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from (3R,4S) tert-butyl-3-hydroxy-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (Step B, Rt 13.686 min) and (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (Example 1, step C) according to the procedure for Example 1, Step D. The product mixture was further purified by preparative HPLC on ChiralPak OD column eluting with heptanes/ethanol (98/2) to obtain the faster moving minor isomer (epimeric at the benzylic methyl position) and slower moving title compound. 1H-NMR (CDCl3): (rotamers): δ: 1.43-47 (2d, 3H, 6.5 Hz), 1.49-1.52 (2s, 9H), 3.3-3.5 (m, 3H), 3.75-3.95 (m, 3H), 4.53 (q, 1H, 6.5 Hz), 6.95 (t, 2H), 7.05 (m, 2H), 7.53 (s, 2H), 7.76 (s, 1H)ppm. MS: 466 (M-t-Bu)+ observed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:13][C:14]([CH2:18]O)([CH2:16]O)[CH3:15]>>[CH3:13][C:14]1([CH3:18])[CH2:16][O:11][B:10]([C:4]2[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[O:12][CH2:15]1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: CC(C)(CO)CO
Product: CC1(C)COB(c2cc(F)c(F)c(F)c2)OC1
Yield: 34 %

Procedure:
The title compound (34%, yellow oil) was prepared from 3,4,5-trifluorophenylboronic acid and neopentylglycol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][C:9]=1B(O)O.Br[C:20]1[CH:21]=[N:22][C:23]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[CH:33]=3)[C:28]([CH2:39][OH:40])=[CH:27]2)=[N:24][CH:25]=1.O>CC(O)(CC)C>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([F:7])=[C:9]([C:20]2[CH:25]=[N:24][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[CH:33]=4)[C:28]([CH2:39][OH:40])=[CH:27]3)=[N:22][CH:21]=2)[CH:10]=1)[CH3:15]
Reactant: CCc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc2c(CO)cn(-c3ncc(Br)cn3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)(C)O
Product: CCc1ccc(F)c(-c2cnc(-n3cc(CO)c4ccc(C(=O)OC)cc43)nc2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (0.915 g, 6.62 mmol) and 2-fluoro-5-ethylphenylboronic acid (0.742 g, 4.14 mmol) were added at room temperature to a solution 331a) (0.8 g, 2.2 mmol) in 2-methyl-2-butanol 1/water (44 mL, 10:1). The reaction apparatus was set under an argon atmosphere and (Ataphos)2PdCl2 (0.156 g, 0.22 mmol) was introduced. The reaction mixture was stirred at 100° C. for 4 h, cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and the remnant purified by flash column chromatography [silica; dichloromethane with 1-2% methanol]. White solid. Yield: 0.5 g (56% of theory)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:31][CH:32]=1)=[O:27]>C(Cl)Cl>[CH3:24][O:25][C:26]([C:28]1[O:29][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:23])[CH2:18][CH2:19]2)(=[O:35])=[O:34])=[CH:31][CH:32]=1)=[O:27]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Diisopropylethylamine (0.75 ml, 4.45 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (0.45 g, 2.26 mmol) in DCM (5 ml) at room temperature. To this mixture was added 5-chlorosulfonyl-furan-2-carboxylic acid methyl ester (0.5 g, 2.26 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was collected by filtration, washed with diethyl ether and dried under vacuum to give the title compound (0.76 g, 88% yield) as an off-white solid. Tr=1.98 min, m/z (ES+) (M+Na)+ 411.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:35][O:36][CH:37]1[CH2:40][NH:39][CH2:38]1.C(Cl)(Cl)Cl>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:39]4[CH2:40][CH:37]([O:36][CH3:35])[CH2:38]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: COC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CC(OC)C4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride in DMF. [α]D20=+42.5° (c=0.44, CHCl3), ES-MS m/e (%): 457 (M+H+, 100).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:17]1[C:11]2[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[C:7]([N:1]3[CH2:2][CH2:3][N:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:5][CH2:6]3)=[N:13][C:12]=2[CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc2c(c1)Cc1ccccc1C(N1CCNCC1)=N2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C2=Nc3ccccc3Cc3ccccc32)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
A mixture of 3.33 g of 6-(1-piperazinyl)-11H-dibenz[b,e]azepine, 1.63 g of ethyl chloroformate and 1.66 g of potassium carbonate in 20 ml of N,N-dimethylformamide was stirred at 80° C. for 3 hrs. Ice water was added to the reaction mixture and extracted with ether. The ether layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (1:2) as an eluent to give 3.14 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless prisms, mp 137°-138° C.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.C1C([C@H]([O:58][C@@H:59]2[O:64][C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)C#N)=CC=C(O)C=1.[OH:71][C:72]1[CH:77]=[CH:76][C:75]([CH2:78][CH:79]=[N:80]O)=[CH:74][CH:73]=1>>[NH2:80][C@H:79]([C:59]([OH:64])=[O:58])[CH2:78][C:75]1[CH:76]=[CH:77][C:72]([OH:71])=[CH:73][CH:74]=1
Reactant: ON=CCc1ccc(O)cc1
Reactant: N#C[C@@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)c1ccc(O)cc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The complete reaction mixtures contain: 3 μl of isolated, recombinant P450TYR (6 pmol, heterologously expressed in E. coli and isolated as in Halkier et al, Arch. Biochem, Biophys. 322: 369-277, 1995), 10 μl isolated and dialyzed P450OX (approximately 0.4 pmol), 5 μl of NADPH-P450 oxidoreductase (0.075 U), 1 μl of partially purified UDPG glucosyl transferase from Sorghum, 5 μl of DLPC (10 mg/ml in 50 mM Kpi (pH7), 0.25 μl of [U- 14C]-tyrosine (0.05 μl Ci/mmol, 443 mCi/mmol, Amersham), 3 μl of UDPG (33 mg/ml in 50 mM Kpi (pH7)), and 3 μl of castanospermin (2 mM in 50 mM Kpi (pH7)). The components are mixed by repeated suspension and if necessary the final volume adjusted to 30 μl by the use of 50 mM Kpi (pH7). The enzyme reaction is initated with 1 μl of NADPH (25 mg/ml). Dhurrin is also synthesized via reconstitution of P450OX with p-hydroxyphenylacetaldehyde oxime (leaving out P450TYR and tyrosine from the reaction mixtures any additonal components being unchanged.). These assays contain either 0.5 μl of [U -14C]-p-hydroxphenylacetaldehyd oxime (0.014 μci/μl, 394 mCi/mmol) or 3 μl of unlabelled p-hydroxyphenylacetaldehyde oxime (20 mM) as substrate for P450OX. In the latter case the radioactive label is 1 μl of [U - 14C]-UDPG (0.025 μCi/μl, 287 mCi/mmol, Amersham). All reaction mixtures are prepared as duplicates. After incubation for 1 h at 30° c. each set of reaction mixture is applied to TLC sheets. The first set of reaction mixtures is analyzed using the ethyl acetate/toluene solvent as in example 4.5. The second set of reaction mixtures is analyzed using a solvent system consisting of ethyl acetate/acetone/dichloromethane/methanol/water (20/15/6/5/4, v/v/v/v/v) in order to achieve seperation of the hydrophilic product dhurrin from tyrosine and from the hydrophobic intermediates. Radiolabelled substrates and products are visulized using the STORM 840-phosphorimager.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([C:14](=O)[CH2:15][Cl:16])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].O>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([CH2:14][CH2:15][Cl:16])[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCc2cc(C(=O)CCl)sc2C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)N1CCCc2cc(CCCl)sc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
A mixture of 2.1 g of 7-acetyl-2-chloroacetyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine in 5.4 ml of triethylsilane and 15 ml of trifluoroacetic acid was stirred at room temperature for 12 hours. The mixture was poured into water, made alkaline and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on a silica gel to give 1.8 g of 7-acetyl-2-chloroethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.