Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:9])[CH3:22]
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-2-chloro-phenol (2.0 g, 9.64 mmol) and anhydrous potassium carbonate (4.0 g, 28.92 mmol) in dry DMF (30 ml) was heated at 60° C. for 1 h under Ar atmosphere. The mixture was then cooled to room temperature and ethyl chloroacetate (1.24 ml, 11.57 mmol) was added through septum using syringe. The mixture was stirred overnight at room temperature and poured into water with stirring. Stirring continued for 10 min, and then partitioned between ethyl acetate and water. The organic phase washed with brine, dried (anhydrous MgSO4), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=15:3:1) to give (4-Bromo-2-chloro-phenoxy)-acetic acid ethyl ester as a colorless oil (2.98 (2.83) g, >100% yield). To (4-bromo-2-chloro-phenoxy)-acetic acid (132.8 mg, 0.5 mmol), 3-amino-benzamide (102.2 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (5 ml) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=10:1) to give 3-[2-(4-bromo-2-chloro-phenoxy)acetyl-amino]-benzamide as a white solid (181.4 mg, 94.6% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[SH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=2[CH:23]=1
Reactant: Sc1ccccn1
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Product: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCSc3ccccn3)cc21

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-pyridine.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:14][C:15]1[CH:35]=[N:34][C:18]2[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)C(=O)[O:21][C:22](=O)[C:17]=2[CH:16]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:19]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:18]2[C:17]([C:22]=1[OH:21])=[CH:16][C:15]([Cl:14])=[CH:35][N:34]=2)=[O:4])[CH3:7]
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3cc(Cl)cnc32)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc(Cl)cnc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
Diethyl malonate (6.02 mL, 71.38 mmol) was added slowly to a suspension of NaH (60% in mineral oil, 3.13 g, 78.24 mmol) in dimethylacetamide (200 mL) and stirred at room temperature for 0.5 h under argon atmosphere. 6-Chloro-1-(4-methoxy-benzyl)-1H-pyrido-[2,3-d]-[1,3]-oxazine-2,4-dione (73) (21.5 g, 71.31 mmol) was added to the solution and heated at 110° C. for 4 h (TLC control). The solution was cooled and poured into ice water. The pH of the solution was adjusted to 3 by cold 10% HCl. The solids formed were filtered, washed by excess water, and dried in a vacuum oven to yield 14.0 g (99%) of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (75) as white solids. MP: 198° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.68 (s, 3H), 4.30 (q, J=7.2 Hz, 2H), 5.43 (s, 2H), 6.81 (m, Hz, 2H), 7.20 (m, 2H), 8.43 (d, J=2.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H); EIMS: 389 (M+1).
Reaction SMILES: [H-].[Na+].CN(C)[CH:5]=[O:6].Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:15][CH2:14][C:13](=[CH2:12])[CH2:5][OH:6])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)C=O
Reactant: ClCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=C(CO)COCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Sodium hydride (from 55-60% oil dispersion (0.52 g) washed with pentane (3×3 ml)), dry dimethylformamide (20 ml), and 2-metyylenepropane-1,3-diol (1.0 g) were mixed. After 1 hour when H2 -evolution had ceased 1-chloro-6-(triphenylmethoxy)hexane (4.2 g) was added, and the mixture was stirred for 3 hours at 85° C. After cooling water (20 ml) was carefully added, and the mixture was extracted with ether (2×100 ml). The ether extracts were washed with water (100 ml), dried over magnesium sulfate and evaporated to dryness in vacuo. The product was purified through a column of silica gel 60 (70-230 mesh, 40 g) eluting with ether. Futher purification was achieved by chromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/pentane 1:2 followed by ether/pentane 1:1 as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Se](=O)=[O:18]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: O=[Se]=O
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: O=C(C(=O)c1ccc(Cl)cc1)c1ccncc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of 25 g of 1-(4-chlorophenyl)-2-pyridin-4-yl-ethanone in 285 ml of dioxan was treated with 20 g of selenium dioxide. The mixture was stirred at 100° C. for 1 hour and filtered. The solvent was evaporated and the residue was dissolved in dichloromethane. The solution was washed three times with water, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in ethyl acetate, the solution was filtered over silica gel and evaporated to yield 23.7 g of 1-(4-chlorophenyl)-2-pyridin-4-yl-ethanedione, m.p. 119-120° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].Cl.Cl.[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][NH:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18]
Reactant: C1CC2CNC1CN2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC3CN4)nc21
Yield: 90.9 %

Procedure:
A solution of 0.54 g (2.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.46 g (2.5 mmole) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 1.05 ml (7.0 mmole) of 1,8-diazabicyclo (5.4.0) undec-7-ene, and 30 ml of acetonitrile was stirred at room temperature for 23 hours. The reaction mixture was filtered and the solid was washed with acetonitrile to give 0.63 g of the title compound, mp 250°-253°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[C:34]([C:35](O)=[O:36])=[CH:33][C:32]2[CH:38]=[CH:39][CH:40]=[CH:41][C:31]1=2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:34]4[S:30][C:31]5[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=5[CH:33]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc3ccccc3s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and benzo[b]thiophene-2-carboxylic acid (27 mg, 0.15 mmol).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[S:12])[NH:11][C:7]=2[CH:6]=1)=[O:4].Br[CH:16](Br)[CH3:17].Cl.[OH-].[Na+]>C(O)C.CN(C=O)C>[S:12]1[CH2:17][CH2:16][N:9]2[C:8]3[CH:13]=[CH:14][C:5]([CH2:3][OH:4])=[CH:6][C:7]=3[N:11]=[C:10]12
Reactant: CC(Br)Br
Reactant: COC(=O)c1ccc2[nH]c(=S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: OCc1ccc2c(c1)nc1n2CCS1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.9 %

Procedure:
To a round bottomed flask was added 2.83 grams of 2-Thioxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester, 2.55 grams of dibromoethane and 50 ml DMF and 50 ml ethanol. The mixture was refluxed for 10 hours. Then it was concentrated to dry on a rotary evaporator. The solid was next dissolved in 100 ml THF and 20 ml of 1 M LiAlH4 (in THF) was next injected within five minutes. The reaction media was stirred at room temperature for one hour. Ethanol was next added (˜10 ml), followed by 50 ml 2N HCl. The aqueous layer was adjusted to basic Ph=14 with 10N sodium hydroxide. The aqueous was extracted with 2×500 ml ethyl acetate. The combined organic layers was dried over magnesium sulfate. Filter off the drying agent and cocentrate yielded 2.04 grams (60%) product. MS: 207.0 (M+H). H-NMR(DMSO): □ 7.34(m, 2H), 7.08 (m, 1H), 5.15(m, 1H, OH), 4.53 (m, 2H, CH2), 4.34 (m, 2H, CH2), 4.00 (m, 2H, CH2).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1

Procedure:
In an analogous manner to that described in Example 22(b), by an elimination reaction from 1-benzyl-4-[4-(2-hydroxy-ethyl)-phenyl]-piperidin-4-ol using p-toluenesulphonic acid there was obtained 2-[4-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-ethanol as a colourless oil; MS: 293 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:24])[CH2:9][NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42]>C(C(C)=O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:24])[CH2:9][NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc([C@@H]2CCC[C@@H](NC[C@H](O)c3cccc(Cl)c3)C2)c1
Reactant: CCOC(=O)CBr
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cccc([C@@H]2CCC[C@@H](NC[C@H](O)c3cccc(Cl)c3)C2)c1

Procedure:
A methyl ethyl ketone mixture liquid of 1 equivalent of (1R)-1-(3-chlorophenyl)-2-[(1R,3R)-3-(3-hydroxyphenyl)cyclohexylamino]ethanol 1/3 toluene-solvate and from 2.0 to 3.0 equivalents of potassium carbonate was heated under reflux. With heating, a methyl ethyl ketone solution of from 1.0 to 1.2 equivalents of ethyl bromoacetate was dropwise added to the mixture liquid, and further heated under reflux for 3 to 4 hours. A part of the reaction liquid was sampled, and subjected to HPLC analysis. After cooled, this was filtered through Celite, and a methyl ethyl ketone solution of 1.0 equivalent of maleic acid was put into the obtained solution, and stirred. The precipitated crystal was taken out through filtration, and dried through aeration to obtain ethyl 3-[(1R,3R)-3-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxyacetate maleate. The obtained crystal was subjected to HPLC analysis, in which the content of (1R)-1-(3-chlorophenyl)-2-[(1R,3R)-3-(3-hydroxyphenyl)cyclohexylamino]ethanol (starting compound) and the content of ethyl 3-[(1R,3R)-3-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxyacetate (target product) in the crystal were determined according to the above-mentioned relative area percentage method.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18]>>[OH:18][C@H:17]([C:16]([CH3:20])([CH3:19])[CH3:15])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CC(C)(C)C=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@H](O)C(C)(C)C

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolone with trimethylacetaldehyde. Slow addition of the aldehyde to the enolate solution over 1 hour at 0° C. gave a 9:1 ratio of the (2R*,3S*) and (2R*,3R*) isomers. The desired isomer was crystallized from 1:1 ether/hexanes, mp=90–2° C. 1H-NMR (CDCl3, 400 MHz): δ 8.04 (m, 1H), 7.23–7.29 (m, 3 H), 4.32 (dq,J=3, 7 Hz, 1H), 3.79 (d,J=10 Hz, 1H), 3.41 (dd, J=3,10 Hz, 1 H), 1.51 (d,J=7 Hz, 3 H), 0.94 (s, 9 H). 13C-NMR (CDCl3, 100 MHz): δ 178.2, 150.8, 142.0, 127.6, 125.7, 125.0, 116.3, 110.0, 84.0, 37.4, 36.2, 26.7, 18.1.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:18]=[C:19]=[O:20])(=O)=O>C(#N)C>[CH2:1]([O:8][CH:9]([CH3:13])[C:10]([NH:12][C:19]([NH2:18])=[O:20])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(OCc1ccccc1)C(N)=O
Solvent: CC#N
Product: CC(OCc1ccccc1)C(=O)NC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a suspension of 2-benzyloxy-propionamide (Helv. Chim. Acta, 1971, 845-851) (26.6 mmol, 4.77 g) in acetonitrile (100 mL) at room temperature was added dropwise chlorosulfonyl isocyanate (26.6 mmol, 4.1 mL) in acetonitrile (20 mL). After 1 h the reaction was concentrated, then carefully quenched with water (20 mL) and allowed to stir at room temperature for 1 h. The precipitated solid was filtered, collected and air-dried to obtain (2-benzyloxy-propionyl)-urea (62%, 3.66 g); NMR 1.2 (d, 3H), 4.0 (t, 1H), 4.4 (dd, 2H), 7.3 (m, 5H), 7.7 (s, 1H), 10.0 (S, 1H). The above reaction conditions were followed to convert (2-benzyloxy-propionyl)-urea to 2-benzyloxy-N-ureidocarbonyl-propionamide, using the above compound, (2-benzyloxy-propionyl)-urea (16.5 mmol, 3.66 g), chlorosulfonyl isocyanate (28.8 mmol, 2.5 mL), and acetonitrile (80 mL). The yield of 2-benzyloxy-N-ureidocarbonyl-propionamide was 59% (2.56 g); NMR 1.4 (d, 3H), 4.2 (t, 1H), 4.6 (dd, 2H), 7.4 (m, 5H), 9.8 (s, 1H), 11.1 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[S:5][C:6]=1[C:7]#[N:8].[NH2:13][CH2:14][CH2:15][OH:16]>CS(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][CH2:14][CH2:15][OH:16])[S:5][C:6]=1[C:7]#[N:8]
Reactant: NCCO
Reactant: CS(=O)(=O)c1nc(N)c(C#N)s1
Solvent: CS(C)=O
Product: N#Cc1sc(NCCO)nc1N
Yield: 116.8 %

Procedure:
Example 89A is prepared in analogy to Example 48A from 4-amino-2-(methylsulphonyl)-1,3-thiazole-5-carbonitrile (Example 18A) (499 mg, 2.45 mmol) and 2-aminoethanol (300 mg, 4.91 mmol) in DMSO (80° C., 20 h). Removal of the solvent results in a crude product 527 mg (50% of theory) which is employed without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:39])[C:29]([CH3:31])([CH3:30])[O:28][B:27]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[O:26]1.CS(C)=O>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([B:27]4[O:28][C:29]([CH3:31])([CH3:30])[C:25]([CH3:39])([CH3:24])[O:26]4)=[CH:38][CH:37]=3)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: O
Solvent: CS(C)=O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 23 %

Procedure:
A 18-mL vial was charged with [2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]trifluoromethanesulfonate (39 mg, 0.1 mmole) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (22 mg, 0.1 mmol) and DMSO (0.5 ml). The resulting mixture was stirred under Ar for 3.5 hr. After cooling to room temperature, water was added to the mixture (5 ml). The precipitate was collected by filtration and the crude product was purified by chromatography on silica gel using hexane/DCM (4:1) followed by 2% of methanol in DCM as eluent to afford the title compound, containing impurities, which was forward to the next step without any further purification (10.3 mg, 23% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10](=[O:11])[O:9][CH:8]([CH2:12][C:13]([O:15]CCCC)=[O:14])[C:7]=2[CH:20]=1>Cl.O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10](=[O:11])[O:9][CH:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7]=2[CH:20]=1
Reactant: CCCCOC(=O)CC1OC(=O)c2ccc(OC)cc21
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1)C(CC(=O)O)OC2=O
Temperature: 80 °C
Yield: 74.9 %

Procedure:
A mixture of butyl (6-methoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl)acetate (251 mg, 0.902 mmol) in 6M HCl/H2O (10.0 ml) was heated at 80° C. for 2.5 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and rotary evaporated to give a pale yellow solid. The pale yellow solid was triturated at room temperature with 10% EtOAc/Hexane and then only hexane to afford (6-methoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl)acetic acid as a white solid (150.2 mg, 75%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=[N:11]O)[CH2:6]2.C([O-])(=O)C.[NH4+]>C(O)C.[Ni]>[NH2:11][CH:5]1[CH2:4][CH:3]2[N:2]([CH3:1])[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6]1
Reactant: CN1C2CCCC1CC(=NO)C2
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1C2CCCC1CC(N)C2
Reaction time: 24 h

Procedure:
N-methyl-9-azabicyclo-[3.3.1]-nonan-3-one oxime (3.25 g., 0.02 mole) was dissolved in ethanol and hydrogenated over Raney nickel in the presence of ammonium acetate at 300 p.s.i. at 50° C. for 24 hours. The mixture was filtered, evaporated in vacuo, dissolved in dilute hydrochloric acid, basified and extracted into ethyl acetate. The combined organic layers were dried (K2CO3), filtered and evaporated in vacuo to yield 3-amino-9-methyl-9-azabicyclo-3.3.1]-nonane (2.67 g., 90%), used without further purification.
Reaction SMILES: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:49])[CH2:39][C@H:40]([OH:48])[C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:50])[CH2:36][CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:51][C@@:28]12[C@H:34]3[CH2:35][CH2:36][C@:37]4([CH3:50])[C@@H:41]([C:42]5[CH2:47][O:46][C:44](=[O:45])[CH:43]=5)[C@@H:40]([OH:48])[CH2:39][C@:38]4([OH:49])[C@@H:33]3[CH2:32][CH2:31][C@@H:29]1[CH2:30][C@@H:25]([OH:24])[CH2:26][CH2:27]2
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5CC[C@]5(C)[C@@H](C7=CC(=O)OC7)[C@@H](O)C[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C3=CC(=O)OC3)[C@@H](O)C[C@]12O
Reaction time: 72 h
Yield: 93.6 %

Procedure:
A suspension of 4.7 grams of gitoxin in 300 ml of ethanol containing 4.7 ml of conc. hydrochloric acid was stirred for three days, warmed gently for ten hours then stirred for another day at room temperature. The acidic solution was neutralized by the addition of solid sodium carbonate, then filtered to yield a clear colorless solution. The solvent was removed on a rotary evaporator and the residue was mulled in water to remove carbohydrate hydrolysis products. The residue was extracted into a solution of 100 ml of ethyl acetate and 30 ml of acetone, then filtered. A product crystallized as the solvent was removed under vacuum. The residue was mulled in ethyl ether to yield 2.2 grams of white crystalline gitoxigenin. On HPLC using system C as in Example 1. gitoxigenin had a retention time of 13.9 minutes, compared to a starting material reference gitoxin at 20.7 minutes. On TLC using system B gitoxigenin showed a blue fluorescent spot at Rf 0.69, compared to gitoxin at Rf 0.23. The product was about 95% pure gitoxigenin.
Reaction SMILES: [Cl:1][CH2:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[S:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1>N1C=CC=CC=1>[Cl:1][CH2:2][S:3]([NH:7][C:8]1[S:9][C:10]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(Cl)CCl
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Solvent: c1ccncc1
Product: O=S(=O)(CCl)Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
2.70 g of chloromethanesulfonyl chloride was dropped into a solution of 2.27 g of 2-amino-4,5-diphenylthiazole in pyridine under stirring at room temperature, and the resulting mixture was stirred as such for 2 hours. Then the reaction mixture was poured into ice-water and the crystals thus precipitated were recovered by filtration and separated with a silica gel column by using isopropyl ether and ethyl acetate as a developer. The crystals thus obtained were recrystallized from isopropyl ether/ethyl acetate to give 1.45 g of 2-chloromethanesulfonylamino-4,5-diphenylthiazole. The melting point of this product was from 201° to 203° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:29][C:28]([CH3:31])([CH3:30])[CH:27]=[CH:26][C:6]2=[C:7]2[C:16]=1[C:15](=[O:17])[C:14]1[CH:13]=[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]3=[C:10]([N+:22]([O-])=O)[C:9]=1[N:8]2[CH3:25].O>C(O)(=O)C.[Zn]>[NH2:22][C:10]1[C:9]2[N:8]([CH3:25])[C:7]3[C:16](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]4[O:29][C:28]([CH3:30])([CH3:31])[CH:27]=[CH:26][C:6]4=3)[C:15](=[O:17])[C:14]=2[CH:13]=[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=12
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4c([N+](=O)[O-])c1n3C)C=CC(C)(C)O2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4c(N)c1n3C)C=CC(C)(C)O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 178 mg of the compound obtained in Step 6 above in 10 ml of acetic acid and 1 ml of water there are added 621 mg of zinc wool. The reaction mixture is stirred at ambient temperature for 2.5 hours and is then filtered. The filtrate is made alkaline using 10% aqueous ammonium hydroxide solution; the precipitate formed is then separated off by filtration. The crude residue is purified by chromatography over silica gel (dichloromethane/methanol: gradient from 0.1 to 0.5%), allowing the expected product to be isolated.