Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].N1C=CN=C1.Cl[Si:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C)C=O.[Cl-].[Na+]>[CH3:25][Si:16]([O:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])([CH3:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC[Si](C)(C)Cl
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCCCC[Si](C)(C)Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.75 g (0.023 mole) 2,5-dichlorophenol in 30 ml N,N-dimethylformamide are added 5.58 g (0.082 mole) imidazole and 16.6 ml (0.070 mole) chlorodimethyloctyl silane under argon. After stirring at room temperature for two hours, the mixture is diluted with an aqueous saturated sodium chloride solution and extracted with ether. The combined organic extracts are dried and condensed. The product is purified by column chromatography.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[S:61][CH:62]=2)=[N:56]\[OH:57])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:85]([O:88][C:89]1[C:97]([O:98][C:99](=[O:101])[CH3:100])=[CH:96][C:92]([C:93](Cl)=[O:94])=[C:91]([CH3:102])[CH:90]=1)(=[O:87])[CH3:86].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[N:32]4[N:33]=[C:34]([C:36]([O:38][CH:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[O:37])[N:35]=[C:31]4[N:30]=[C:29]([CH3:52])[CH:28]=2)[C@H:20]([NH:53][C:54](=[O:83])/[C:55](/[C:58]2[N:59]=[C:60]([NH:63][C:64]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)([C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[S:61][CH:62]=2)=[N:56]\[O:57][C:93](=[O:94])[C:92]2[CH:96]=[C:97]([O:98][C:99](=[O:101])[CH3:100])[C:89]([O:88][C:85](=[O:87])[CH3:86])=[CH:90][C:91]=2[CH3:102])[C:19]3=[O:84])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Reactant: CC(=O)Oc1cc(C)c(C(=O)Cl)cc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)c(C(=O)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4cc(C)nc5nc(C(=O)OC(c6ccccc6)c6ccccc6)nn45)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To an ice-cooled solution of (6R, 7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (0.7 g) in dry dichloromethane (10 ml) was added 4,5-diacetoxy-2-methylbenzoyl chloride (0.19 g) at once and then potassium carbonate (0.083 g). The yellow suspension was stirred at 0° C. for 30 minutes, the insoluble matters were removed by filtration, and the filtrate was washed with brine and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, and the residue was crystallized with ether (20 ml), giving 0.80 g of the objective compound as pale yellow crystals.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.[BH4-].[Na+]>CO.C(O)(=O)C>[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34][NH:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NCc3ncc[nH]3)s2)cc1C#N
Temperature: 55 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Prepared using General Procedure 11. To (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (25 mg, 0.06 mmol) and 1H-imidazole-2-carbaldehyde (6.4 mg, 0.06 mmol) in anhydrous MeOH (1 mL) was added acetic acid (1 drop). The solution was stirred at 55° C. for 3 h before cooling to room temperature and the addition of NaBH4 (4.6 mg, 0.12 mmol). The mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (0.5 mL) and partitioned between EA (5 mL) and water (5 mL). The organic layers washed with water and brine, and the product purified by preparative HPLC to afford 22 mg (81%) of (S)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 28 as half-white solid. LCMS-ESI (m/z) calculated for C25H24N6OS: 456.2; found 457.2 [M+H]+, tR=2.38 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(O)cc1O
Reaction time: 16 h

Procedure:
1.1 80 g of 5-bromo-2,4-dihydroxybenzoic acid are initially introduced in 1 l of methanol, 8 ml of sulfuric acid are added, and the mixture is boiled for 16 hours. The solvent is removed, the residue is taken up in MTB ether, and the solution is subjected to conventional work-up, giving 80 g of methyl 5-bromo-2,4-dihydroxybenzoate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[O:1]([CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Br:10])[CH:7]=[CH:8][CH:9]=1)[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cccc(Br)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 3-(2-hydroxyethyl)bromobenzene (4.0 g, 20 mmol) in methylene chloride (100 ml) at 0° C. was added a solution of tert-butyldimethylsilyl chloride (3.6 g, 24 mmol), dimethylaminopyridine (0.61 g, 5 mmol) and triethylamine (3.6 ml, 25.9 mmol). After 1 h, the reaction mixture was washed with brine, saturated ammonium chloride, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 0-10% hexane/ethyl acetate) to give 3-(2-tert-butyl-dimethylsiloxyethyl)bromobenzene (6.0 g).
Reaction SMILES: [F-:1].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[N:24][CH:23]=1.C(OCC)(=O)C>C(#N)C.C1(C)C=CC=CC=1.O>[F:1][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[N:24][CH:23]=1
Reactant: [F-]
Reactant: N#Cc1cncc(Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#Cc1cncc(F)n1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
In a mixture of 140 ml of acetonitrile and 280 ml of toluene were suspended 58 g of potassium fluoride (spray-dried) and 8.7 g f 18-crown-6-ether. After heating the suspension under reflux for one hour in an atmosphere of nitrogen gas, the acetonitrile and toluene were distilled off under atmospheric pressure. The residue thus obtained was suspended in 280 mL of acetonitrile, 23 g of 6-chloro-2-pyrazinecarbonitrile synthesized according to the method described in Acta Poloniae Pharmaceutica, Vol. 33, Pages 153-161 (1976) was added, and the mixture thus obtained was heated under reflux for one hour in an atmosphere of nitrogen. The reaction mixture was cooled to room temperature, 280 mL of ethyl acetate and 280 mL of water were added, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was distilled off under a reduce pressure. The residue was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 10 g of 6-fluoro-2-pyrazinecarbonitrile as a white-colored solid product.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[NH3:24]>>[C:1](=[NH:24])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N
Agent: O=C(O)c1ccccc1
Product: N=C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 65 %

Procedure:
91.1 Grams of benzophenone and 0.1 g of benzoic acid were charged into a pressure reactor, and an ammonia gas under 8 atmospheres was continuously fed to the reactor through a gas dispersing plate at a feed rate of 2 l/min. at a reaction temperature of 200° C. Reaction was carried out for 2 hours. As a result, benzophenoneimine was obtained in yield of 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[OH2:11].OO>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:11])=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10]
Reactant: O
Reactant: COc1c(Cl)ccnc1C
Agent: OO
Solvent: CC(=O)O
Product: COc1c(Cl)cc[n+]([O-])c1C
Temperature: 90 °C

Procedure:
36.98 g of 4-chloro-3-methoxy-2-methylpyridine (V) was dissolved in 685 ml of acetic acid and 92 ml of hydrogen peroxide water was added thereto and the resulting mixture was heated at 90° C. for 24 hours, and thereafter, the reaction solution was distilled off under reduced pressure. The resulting residue was dissolved in chloroform and washed with saturated sodium bicarbonate solution, and saturated salt water, and thereafter, dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 37.64 g of 4-chloro-3-methoxy-2-methylpyridine N-oxide (VI).
Reaction SMILES: C(O[C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:5]=1)C.C(N(CC)CC)C.C=C(Cl)[Cl:39]>ClCCl>[Cl:39][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:5]=1
Reactant: C=C(Cl)Cl
Reactant: CCOc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1
Reaction time: 16 h

Procedure:
The product from Example 70, part d) (50 mg, 0.14 mmol) was suspended in vinylidine chloride (5 ml) with triethylamine (43 mg, 0.42 mmol). The reaction was stirred for 16 hours, diluted with dichloromethane and washed with 5% ammonia solution and then dried (MgSO4), filtered and evaporated to yield a solid which was purified by preparative thin layer chromatography using methanol/dichloromethane (3:97) as elutant to yield 12.5 mg of pure product, 1H NMR (360 MHz, CDCl3) 8.66-8.72 (2H, m), 8.35 (1H, d, J=7 Hz), 7.98 (1H, t, J=7 Hz), 7.85 (1H, t, J=7 Hz), 7.80-7.70 (2H, m), 7.28 (1H, m), 7.03 (1H, s), 5.76 (2H, s); MS (ES30) 379 [MH]+.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[Si:5]([O:12][C@@H:13]1[CH2:17][C:16](=[O:18])[CH:15]=[CH:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>CO>[Si:5]([O:12][CH:13]1[CH:17]2[C@@H:16]([O:18]2)[C:15](=[O:1])[CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)[C@@H]2OC12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Hydrogen peroxide (4.5 mL, 46.3 mmol, 30% by wt.) and 1N NaOH (46 μL, 0.046 mmol) were added to a solution of enone 2 (2.5 g, 11.5 mmol) in MeOH (30 mL) at 0° C. After stirring 1.5 h at 0° C. the mixture was concentrated in vacuo, washed with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the above titled compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH:12]2[CH2:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:13]2)[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO.O>[O:17]=[C:15]1[N:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[CH2:13][CH:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16]1
Reactant: CCOC(=O)c1cnn(CC2CC(=O)N(c3cccc(C(F)(F)F)c3)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(CC2CC(=O)N(c3cccc(C(F)(F)F)c3)C2)c1
Temperature: 100 °C
Yield: 88 %

Procedure:
To a stirred solution of 1-[5-Oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (2.6 g, 6.81 mmol) in 14 mL MeOH:H2O (3:11), NaOH (0.4 g, 10.5 mmol) was added at room temperature. The mixture was heated at 100° C. for 2 h. The reaction mixture was cooled; MeOH was removed under reduced pressure, diluted with water, washed with DCM and acidified with 1% HCl. The acidified mixture was extracted with EtOAc (3×50 mL) and the combined extract was washed with brine, dried with Na2SO4, evaporated under reduced pressure to give the title compound in 88% yield (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([Cl:11])[C:3]=12.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1cnc2[nH]cnc(Cl)c1-2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Cl)c2c(Cl)ncnc21
Reaction time: 0.33 h

Procedure:
To a solution of 4,5-dichloro-1H-pyrrolo[2,3-d]pyrimidine D39 (1 g) in DMF (20 ml) at 0° C. was added sodium hydride (60% w/w in mineral oil, 255 mg, 6.4 mmol) and the mixture stirred for 20 mins. Phenylsulfonyl chloride (1.31 g, 7.4 mmol) was the added dropwise and the reaction mixture was kept in a cool bath for 15 hours. The mixture was poured into water (40 ml), and the precipitate was filtered, washed with water and Et2O, dried in a vacuum to give the desired product D40 in 1.62 g as an ashen solid. LCMS [MH+] 329.9@1.77 min (5 min run)
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH3:19].BrC[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([O:24][C:22](=[O:23])[CH2:19][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Br:1])[CH3:26]
Reactant: COc1ccc2c(-c3ccccc3F)noc2c1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Br
Temperature: 65 °C

Procedure:
A mixture of 11.6 g of 7-bromo-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, 17.5 g of ethyl bromoacetate, 13.3 g of potassium carbonate and 100 ml of dimethylformamide is heated at 65° C. for 5 hr. The reaction mixture is poured into water and the mixture is extracted with ether. The ether extracts are washed, dried and evaporated to afford ethyl{[7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6yl]oxy}acetate, mp 130°-131° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]2[C:14](=[O:19])[O:15][C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O>CS(C)=O>[CH3:1][N:17]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:7])[C:13]=2[C:14](=[O:19])[O:15][C:16]1=[O:18]
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1c(=O)oc(=O)c2c(Cl)cccc21
Reaction time: 0.2 h

Procedure:
Anhydrous potassium carbonate (16.8 g.) was added gradually to a suspension of the known compound 1,2-dihydro-5-chloro-2,4-dioxo-3,1-(4H)-benzoxazine (11.7 g.) in dry dimethyl sulphoxide (110 ml.) and the mixture stirred at room temperature for 20 minutes Dimethyl sulphate (7 ml.) was added dropwise with vigorous stirring at 30°-35° for 12 minutes and the mixture allowed to settle. The supernatant liquid was decanted into an ice/dilute hydrochloric acid mixture (600 ml.; 0.05 M.HCl). The resulting precipitate was collected, washed with water and dried in vacuo to give 1,2-dihydro-1-methyl-5-chloro-2,4-dioxo-3,1-(4H)-benzoxazine m.p. 199°-201° (dec.).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([O:55][C:56]([NH:58][CH2:59][C:60](O)=[O:61])=[O:57])([CH3:54])([CH3:53])[CH3:52]>O1CCCC1>[C:51]([O:55][C:56]([NH:58][CH2:59][C:60]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:61])=[O:57])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Yield: 61 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycine. Yield 61%. [α]D 32 +1.2° (c=0.86, tetrahydrofuran).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].O.[C:14]1(C)C=CC(S(O)(=O)=O)=C[CH:15]=1>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH2:14][CH3:15])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(C(=O)O)cc1O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(OC)c(O)c1

Procedure:
A solution of 3-Hydroxy-4-methoxybenzoic acid (25 g, 148.67 mmol) and p-Toluenesulfonic acid monohydrate (3.17 g, 16.66 mmol) in abs ethanol (300 ml) was refluxed for 6 hours or until all the starting material is consumed. The reaction mixture was concentrated, diluted with EtOAc (60 ml) and washed with water (20 ml). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([NH:26][C:14]([C:1]3[C:13]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:15])[CH:27]=[CH:28][CH:29]=2)[CH:22]=1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Reactant: Cc1cn(-c2cccc(N)c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cn(-c2cccc(NC(=O)c3cccc4c3Cc3ccccc3-4)c2)cn1
Reaction time: 24 h
Yield: 29.2 %

Procedure:
To a suspension of 9H-fluorene-1-carboxylic acid (79 mg) and 3-(4-methylimidazol-1-yl)aniline (65 mg) in dichloromethane (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (101 mg) and 4-dimethylaminopyridine (23 mg), and the mire was stirred for 24 hours. The mix e was diluted with dichloromethane, washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4-methylimidazol-1-yl)-phenyl]-9H-fluorene-1-carboxamide (40 mg, 29.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.CC([O-])=O.[Na+].[Br:14]Br>ClCCl>[Br:14][C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: COc1ccccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a suspension of 2-methoxypyridine (1-1) (3.96 kg; 36.3 mol), NaOAc (3.57 kg; 39.9 mol), and dichloromethane (22 L) was added a solution of bromine (2.06 L; 39.9 mol) in dichloromethane (2 L), maintaining the reaction temperature below 7° C. over 2-3 hours. The mixture was aged for 1 hour at 0-7° C. and stirred at room temperature overnight. The reaction mixture was filtered and rinsed with dichloromethane (about 5 L). The filtrate and washings were combined, washed with cold 2 M NaOH (22 L; pH should be below 8) maintaining the temperature below 10° C., and with cold water (11 L). The organic layer was separated and concentrated under reduced pressure to give a crude product 1-2 (6.65 kg). The crude product was purified by vacuum distillation to give pure 1-2 (5.90 kg, 86%). Known compound: G. Butora et al., JACS, 119, 7694-7701 (1997).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[C:21]([CH2:22][C:23](O)=O)=[CH:20][C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2>>[S:17]1[C:21]([CH2:22][CH2:23][N:13]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:11]2)[CH2:14][CH2:15][CH3:16])=[CH:20][C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2
Reactant: O=C(O)Cc1cc2ccccc2s1
Reactant: CCCNC1CCc2cccc(OC)c2C1
Product: CCCN(CCc1cc2ccccc2s1)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis works according to the preparation of A4-1 or A4-4 when using N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and 2-benzo[b]thienyl acetic acid (A3-10: R=OMe, Cy=2-benzo[b]thienyl) (purchasable from Rare Chemicals, Kiel (Germany); order number: GT HW 0344) and subsequent reaction according to the synthesis of A5-1.