Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[C:18]([OH:23])=[N:19][CH:20]=[CH:21][CH:22]=1>>[OH:23][C:18]1[C:17]([NH:16][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Nc1cccnc1O
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O)c2c1C

Procedure:
Prepared analogously to example III using 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 3-amino-2-hydroxypyridine
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1.[Br:17]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2oc3ncccc3c(=O)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=c1c2cc(CBr)ccc2oc2ncccc12
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A mixture of 42 g of 7-methyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine, 36 g of N-bromosuccinimide, 0.4 g of benzoyl peroxide and 420 ml of carbon tetrachloride is refluxed with stirring under ultraviolet light for 2 hours. The reaction mixture is filtered rapidly while it is hot. The crystals thus obtained are suspended in hot water (about 60°C). The suspension is stirred thoroughly, and filtered. The crystals are recrystallized from dioxane to give 47.1 g of 7-bromomethyl-5-oxo-5H-[1]benzopyrano[2,3-b]-pyridine melting at 211°-212.5°C.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+]>O>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: OCC(F)(F)C(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)F)cc1
Temperature: 50 °C
Yield: 79.1 %

Procedure:
2,2,3,3-tetrafluoropropanol(406 g, 3.08 mol), 613 g tosyl chloride(3.22 mol), and 1200 ml water heated to 50° C. with mechanical stirring. Sodium hydroxide(139.7 g, 3.5 ml) in 560 ml water was added at a rate such that the temperature remained less than 65° C. After the addition was completed, the mixture was stirred at 50° C. until the pH of the aqueous phase was 6. The mixture was cooled and extracted with 1.5 liters methylene chloride. The organic layer was washed twice with 200 ml aqueous ammonia, 350 ml water, dried with magnesium sulfate, and distilled to give 697.2 g(79%) viscous oil.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([OH:13])=O)=[N:5]1)([CH3:3])[CH3:2].[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([NH:40][CH2:39][CH2:38][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2ccn(C(C)C)n2)CC1
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)NCCN2CCCC2)c2ccn(C(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
(±)-3-(1-Isopropyl-1H-pyrazol-3-yl)-3-[4-(7-methoxyquinolin-8-yl)-1,4-diazepan-1-yl]propanoic acid (220 mg, 0.50 mmol) and 2-(pyrrolidin-1-yl)ethanamine (114 mg, 1.0 mmol) were suspended in anhydrous DMF (6 mL). N,N-Diisopropylethylamine (0.2 mL, 1.2 mmol) was added and the mixture was stirred at ambient temperature for 5 min followed by addition of HATU (300 mg, 0.79 mmol). After 1 h at ambient temperature, LC-MS and TLC indicated completion of reaction (LC/MS [M+H]+ 534.6). Water (5 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (3×30 mL) and concentrated. The residue was purified by silica gel chromatography using 2 to 5% MeOH in CH2Cl2 containing 0.5% aqueous NH4OH to afford the title compound (230 mg, 86%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.20 (br, 1H), 8.81 (d, 1H, J=2.8 Hz), 8.03 (d, 1H, J=8.4 Hz), 7.51 (d, 1H, J=8.4 Hz), 7.34 (d, 1H, J=2.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.0 and 8.0 Hz), 6.16 (s, 1H), 4.52 (septet, 1H, J=6.8 Hz), 4.34 (br, 1H), 3.90 (s, 3H), 3.58 (m, 2H), 3.52-3.40 (m, 4H), 3.20-2.80 (m, 4H), 2.63 (t, 2H, J=6.8 Hz), 2.54 (br s, 4H), 2.20 (br s, 2H), 2.02 (m, 2H), 1.78 (br s, 4H), 1.47 (d, 6H, J=6.8 Hz). MS (ES) m/z 534.6 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18]>>[F:9][C:5]1[CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]([F:1])=[CH:7][C:6]=1[O:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: OCc1cccc(F)c1
Product: O=[N+]([O-])c1cc(F)c(OCc2cccc(F)c2)cc1F
Yield: 55 %

Procedure:
Prepared in analogy to example 1a) from 2,4,5-trifluoronitrobenzene and 3-fluoro-benzyl alcohol. Colorless solid. Yield=55%. MS: m/e=283.1 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13]CC(=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:18].[O:19]1[CH2:23][CH2:22][CH2:21]C1>>[CH2:1]([N:8]1[CH2:9][CH2:10][C:23](=[O:19])[C:22]([CH3:21])([CH3:18])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CI
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 60 °C

Procedure:
1-Benzylpiperid-4-one (9.45 g, 8.92 mL, 49.98 mmol, 1.0 eq) was added to a suspension of sodium hydride (3.50 g of a 60% suspension in oil, 87.50 mmol, 1.75 eq) in tetrahydrofuran (100 mL). Iodomethane (9.84 g, 3.93 mL, 62.96 mmol, 1.26 eq) was added and the reaction heated to 60° C. for 5 hours. The reaction was filtered and the filtrate concentrated. The residue was partitioned between EtOAc (150 mL) and water (150 mL). The aqueous phase was extracted with EtOAc (150 mL). The organics were combined, washed with brine (150 mL), dried (Na2SO4), and concentrated under reduced pressure. Column chromatography (silica, 20→60% EtOAc-hexane) yielded the title compound as a colourless oil; 1H nmr (CDCl3) δ 7.36-7.26 (5H, m, C6H5), 3.56 (2H, s, CH2C6H5), 2.72 (2H, t, J 6.0 Hz, pipH-5 or H-6), 2.51 (2H, t, J 6.0 Hz, pipH-5 or H-6), 2.41 (2H, s, pipH-2), 1.13 (6H, s, 2×CH3); and 1-benzyl-3-methylpiperidin-4-one (3.12 g) as a colourless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:15][CH:14]=1
Reactant: COc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(OC)cc1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a mixture of aluminum chloride (59.0 g) and dichloromethane (500 ml), ethyl chloroglyoxylate (45.4 ml) was added dropwise at 0° C. After stirring for 15 minutes, anisole (40.1 ml) was added dropwise at 0° C., and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was poured onto ice (500 g), and the mixture was stirred for 1 hour at room temperature The dichloromethane layer separated was washed with saturated aqueous sodium chloride, dried (MgSO4), and then concentrated. The residue was subjected to column chromatography on silica gel, and ethyl 4-methoxyphenylglyoxylate (43.6 g, yield 60%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CC(O)C.C(N(CC)CC)C>CCCCCCC>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][N:27]3[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH3:3])=[CH:13]2
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) (150 g; 90% ee) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (216 g, 1.8 equiv) were charged to a round bottom flask followed by addition of IPA (1.2 L; 8 vol) and triethylamine (175 mL; 2.5 equiv). The resultant slurry was stirred at reflux for one day. Heptane (1.5 L; 10 vol) was added dropwise over two hours. The batch was then cooled to 0-5° C., held for one hour and filtered. The cake was washed with heptane (450 mL; 3 vol) and returned to the reactor. IPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added and the resultant slurry stirred at 20-25° C. for three and half hours then filtered. The cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol) and then vacuum dried at 48° C. for two and half days to give 227 g (90.1%) of the intermediate (Compound 10) as an off-white solid with >99% (AUC) purity and >94% ee (chiral HPLC). The ee was determined by converting a sample of the cake to the final product and analyzing it with chiral HPLC.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH:11]([O-:13])=O.[NH4+:14]>C(O)=O.O.[OH-].[Na+]>[C:4]1([C:2]2[N:14]=[CH:11][O:13][CH:1]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C[O-]
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: c1ccc(-c2cocn2)cc1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
A solution of phenacyl bromide (4 g, 20.1 mmol) and ammonium formate (4.4 g, 70.35 mmol) in formic acid (20 mL) was refluxed for 5 h. The deep red mixture was cooled to r.t., diluted with water and basified with dilute sodium hydroxide solution. This was extracted with ethyl acetate (×3), then the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (60-120 mesh), eluting with 20% ethyl acetate-petroleum ether, to afford 4-phenyloxazole (1 g, 34%) as a pale yellow oil which solidifies at −20° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O>[Si:15]([O:14][CH2:13][CH2:12][O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a solution of the product of Example 2 (670 mg, 2.18 mmol) dissolved in anhydrous THF (22 mL) was added a solution of LAH (1.0 M solution in THF, 2.18 mL, 2.18 mmol) dropwise. After completion of addition the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water. The aqueous layer was extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to provide an oil (587 mg, 1.98 mmol), which was used in the next step without any further purification (91% yield). 1H (CDCl3 7.34 (4H, s), 4.68 (2H, s), 4.57 (2H, s), 3.80, 600 MHz): δ (2H, t, J=5.2 Hz), 3.56 (2H, t, J=5.3 Hz), 1.69 (1H, br s), 0.90 (9H, s), 0.07 (6H, s); 13C (CDCl3 140.4, 138.3, 128.0, 127.2, 73.2, 71.9, 65.4, 150 MHz): δ 63.0, 26.2, 18.6, −5.0.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].COC1C=CC(CCN2CCC[C@H]2C[N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][S:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)=CC=1.[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([N:50]2[CH2:54][CH2:53][CH2:52][C@H:51]2[CH2:55]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:49])=[O:48])=[CH:43][CH:42]=1>CCCCCC.COCCOC>[CH3:40][C:41]1[CH:42]=[CH:43][C:44]([S:47]([N:50]2[CH2:54][CH2:53][CH2:52][C@H:51]2[CH2:55][N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][S:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)(=[O:48])=[O:49])=[CH:45][CH:46]=1
Reactant: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
Lithium diisopropylamide (4.3 ml of a 1.5M solution in hexane) was added to a solution of 5,11-dihydrodibenzo[b,e][1,4]thiazepine (see Example 1 for source) (1.0 g) in DME (25 ml) and the mixture stirred at room temperature for 15 minutes, treated with (S)-1-(4-methylphenylsulphonyl)-2-(4-methylphenylsulphonyloxymethyl)pyrrolidine (3.9 g) (prepared by the method of P. Karrer and K. Ehrhardt, Helv. Chim. Acta, 34, 2202 (1951)), heated under reflux for 2.5 hours, allowed to cool to room temperature, quenched with 2M hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution initially using hexane as eluant and changing to hexane/ethyl acetate (90:10). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless solid, (0.93 g, 44%), m.p. 88°-90° C., [α]589 25 -115° (c=0.62 in ethanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21].[K].CP(Cl)(CC)=O.CN(C)C1C=CC=CC=1.[P]>C(Cl)Cl.C(O)CCC>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CCP(C)(=O)Cl
Agent: [K]
Agent: [P]
Solvent: CCCCO
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 14.9 g of penicillin-G-potassium in 60 ml of absolute methylene chloride, 5.06 g (=40 mmols) of methylethylphosphinic acid chloride and 10 ml of dimethylaniline were added in the same manner as indicated in Example 1. The mixture was stirred for 1 hour and the solution of the mixed anhydride so prepared was converted at -5°C with 9.0 g (= 43 mmols) of phosphorus of pentachloride into the imidochloride. After addition of 60 ml of n-butanol and 2 ml of N,N-dimethylaniline, the mixture was stirred at -5°C for 30 minutes. 60 ml of ice water were added and the 6-aminopenicillanic acid was separated at pH 4. 6.47 g (= 76.4 % of the theory) of 6-aminopenicillanic acid were isolated in the form of colorless crystals having a melting point of 195°C (decomposition) which are identical with authentic 6-aminopenicillanic acid according to the IR-spectrum and the mixed melting point.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=[O:14])[NH:13][C:7]2=[CH:6][CH:5]=1)=[O:10].[CH3:16]I>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:16])[C:12](=[O:14])[O:11][C:9](=[O:10])[C:8]=2[CH:15]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
In a 3 L, 3 neck RBF equipped with mechanical stir, addition funnel, thermocouple and N2 inlet, NaH (30.4 g) was suspended in anhydrous THF (400 mL). While stirring at room temperature, a suspension of 5-chloroisatoic anhydride in THF (400 mL) was added in portion-wise manner over 45 min. The reaction mixture was stirred for 50 min (reaction temperature went up from 18 to 28° C.). To this was added CH3I (285 g, 125 mL) over 15 min. The mixture was then stirred at 42° C. for 16 h. Because TLC showed that some unreacted starting material was still present in the reaction mixture, an additional 30 mL of CH3I was added and the reaction mixture stirred at 42° C. for an additional 3 h. Reaction mixture was cooled (RT) and quenched by the slow (40 min) addition of AcOH (55 mL). Reaction mixture was concentrated to give 275 g thick syrupy product, which was used without any further purification. 1H NMR (300 MHz, CDCl3) δ 3.35 (s, 3H), 7.54 (d, 1H), 7.85 (d, 1H), 7.90 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].[C:8]([OH:17])(=[O:16])[C@H:9]([C@@H:11]([C:13]([OH:15])=[O:14])[OH:12])[OH:10].O1CCOCC1>O>[NH:1]1[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:13]([C@H:11]([C@@H:9]([C:8]([O-:17])=[O:16])[OH:10])[OH:12])([O-:15])=[O:14]
Reactant: O=C(O)C1CCN1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCN1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]

Procedure:
The method described in Example 1 above was followed using DL-AzeOH (2.9 g; 29 mmol), D-tartaric acid (4.3 g; 29 mmol), 1,4-dioxane (5.5 g) and water (4.5 g) to yield 3.4 g (109%, as calculated from the theoretical yield) of L-AzeOH-D-tartrate with a d.e. of 73%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:33][CH3:34])=[O:14]
Reactant: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Reactant: CCCNCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCN(CCC)C(=O)Cc1cccc([N+](=O)[O-])c1C
Reaction time: 0.5 h

Procedure:
A mixture of 22.0 g (0.105 mole) of 2-methyl-3-nitrophenylacetic acid (V. Askam et al., J. Chem. Soc. (C) 1969 1935) and 25 cc of thionyl chloride was slowly heated to 75° and the copious evolution of gasses allowed to moderate. The temperature was raised and the solution was refluxed for 1 hour. The reaction was concentrated in vacuo. The residual straw-colored syrup was chased several times with dry toluene, diluted with 100 cc of dry toluene and added to a cool (10°) mixture of 13 g of sodium carbonate in 150 cc of water and 150 cc of toluene containing 14.5 cc (10.6 g, 0.12 mole) of di-n-propylamine with very slow stirring. After 30 minutes, the ice-bath was removed. Stirring was continued for one hour. An additional 0.5 g of solid sodium carbonate was added to the reaction. After 15 minutes, the organic phase was separated, washed with 5% aqueous sodium carbonate followed by 2N hydrochloric acid and, finally water. The organic solution was dried over magnesium sulfate, concentrated in vacuo and pumped free of solvent to give 29.5 g of 2-methyl-3-nitrophenyl-N,N-di-n-propyl acetamide as a straw-colored syrup.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16]>C(Cl)Cl>[CH3:18][CH:14]1[CH2:19][C:9]2[C:10](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:15]1=[O:16]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Cc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)CC(C)C2=O
Yield: 93 %

Procedure:
107 g (810 mmol) of AlCl3 were slowly added to a solution of 34.4 g (324 mmol) of m-xylene (99% pure) and 74 g (324 mmol) of 2-bromoisobutyryl bromide (98% pure) in 600 ml of analytical grade methylene chloride via a solids metering funnel at room temperature, while stirring vigorously, whereupon vigorous evolution of gases started. The mixture was stirred at room temperature 15 hours, poured onto ice-water, which was acidified with 25 ml of concentrated HC1, and extracted several times with ether. The combined organic phases were washed first with a saturated NaHCO3 solution and then with a saturated NaC1 solution, and dried with magnesium sulfate. The oil which remained after the solvent had been stripped off under reduced pressure was distilled over a short distillation bridge. 52.4 g of the indanone 1 passed over at 81°-90° C./0.1-0.2 mbar in the form of a colorless oil, which crystallized at room temperature. The yield was 93%.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CCOCC>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCOC(=O)C=Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 30 ml of anhydrous ether solution containing 5 g of ethyl 4-hydroxycinnamate was added 7.1 ml of dihydropyran and 50 mg of p-toluenesulfonic acid were added, the mixture was stirred at a room temperature for 2 hours, the reaction mixture was neutralized with 1%-sodium hydroxide solution, washed with water, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation to yield 6.8 g of ethyl 4-(2-tetrahydropyranyloxy)cinnamate. Colorless indefinite form crystals. Melting point: 52°-53° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([OH:21])=O)[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9].C(OC(Cl)=O)C.C(N(CC)CC)C.[OH-:35].[K+].Cl.[NH2:38]O>O1CCCC1.CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]([NH:38][OH:35])=[O:21])[CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2ccco2)c1
Reactant: [OH-]
Reactant: NO
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2ccco2)c1)NO
Reaction time: 0.25 h

Procedure:
To a solution of 3-{3-[(furan-2-ylmethyl)-sulfamoyl]-phenyl}-acrylic acid (5z) (0.17 g, 0.55 mmol) in tetrahydrofuran (2.0 ml) at 0° C. temperature ethylchloroformate (0.072 g 0.66 mmol) and triethylamine (0.1 ml, 0.72 mmol) were added and the resulting mixture was stirred for 15 min. To a stirred solution of KOH (0.058 g, 1.04 mmol) in methanol (0.25 ml) a solution of hydroxylamine hydrochloride (0.072 g, 1.04 mmol) in methanol (0.7 ml) was added at 0° C. The mixture was stirred for 15 min., the precipitated KCl was removed and the filtrate was added to the first solution. The reaction mixture was stirred at room temperature for 2 hours. Then the mixture was partitioned between 1N KH2PO4 solution and ethyl acetate. The organic layer was washed with water, saturated NaCl, and dried (Na2SO4). The solvent was evaporated and the residue was washed successively with dichloromethane and ethyl acetate affording the title compound (0.057 g, 32%), M.p. 165° C., 1H NMR (DMSO-d6, HMDSO) δ: 4.03 (2H, d, J=6.4 Hz); 6.23 (2H, m); 6.54 (1H, d, J=16.0 Hz); 7.38-8.05 (6H, m); 8.20 (1H, t, J=6.4 Hz); 9.09 (1H, br s); 10.83 (1H, br s). HPLC analysis on Zorbax SB-C18 column: impurities 8% (column size 4.6×150 mm; mobile phase methanol—0.1% H3PO4, gradient from 30 to 90%; detector UV 270 nm; flow rate 1.5 ml/min; sample concentration 1.0 mg/ml). Anal. Calcd for C14H14N2O5S, %: C 52.17, H 4.38, N 8.69. Found, %: C 51.87, H 4.39, N 8.41.