Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[Si:13]([O:20][CH2:21][C@H:22]([CH3:25])[CH:23]=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CCOCC>[Si:13]([O:20][CH2:21][C@H:22]([CH3:25])[CH:23]=[N+:8]([O-:9])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: ONCc1ccccc1
Reactant: C[C@H](C=O)CO[Si](C)(C)C(C)(C)C
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCC
Product: C[C@H](C=[N+]([O-])Cc1ccccc1)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a mixture of N-benzylhydroxylamine prepared by the method as described in J. Am. Chem. Soc., 93, 2897 (1971) (368 mg; 3.0 mmol) and calcium chloride (3.30 mg; 3.0 mmol), anhydrous ether (30 ml) was added in argon stream, and (S)-(+)-3-(t-butyldimethylsilyloxy)-2-methylpropanal (600 mg; 3.0 mmol) was added dropwise thereto at 0° C. Stirring was continued at the same temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The oily residue was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (5:5-0:10) to give (R)-(-)-N-(3-t-butyldimethylsilyloxy-2-methylpropylidene)benzylamine-N-oxide (658 mg; 64%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH3:5].[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1>>[Br-:1].[CH2:2]([N+:9]1[CH:10]=[CH:11][N:7]([CH3:6])[CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Cn1ccnc1
Reactant: CCCCBr
Product: CCCC[n+]1ccn(C)c1
Product: [Br-]
Temperature: 80 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
1-bromobutane (110 mmol, 15.07 grams) and 1-methylimidazole (100 mmol, 8.21 grams) were added to a 250 mL flask. The reaction mixture was stirred for 48 hours at 80° C. The resulting ionic liquid was then cooled, washed with ether (3×25 mL) to remove unreacted starting materials, and the product was dried under vacuum at 80° C. for 4 hours to afford 1-butyl-3-methylimidazolium bromide [BMIMBr] in a yield of 93% with 96% purity. The procedure was repeated using 1-chlorobutane and 1-iodobutane to give the corresponding chloride and iodide salts.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH:12]=[CH:13][CH2:14][CH3:15].C(NC(C)C)(C)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:10][C:4]1[CH:3]=[C:2]([CH:13]([CH2:14][CH3:15])[CH2:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:6]([OH:8])[C:5]=1[F:9]
Reactant: CCC=CC(=O)OCC
Reactant: Oc1cc(Br)cc(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(CC)c1cc(O)c(F)c(F)c1
Temperature: 120 °C
Yield: 87 %

Procedure:
A mixture of 5-bromo-2,3-difluorophenol (20 g 0.0957 mol), ethyl pentenoate (24.53 g, 0.191 mol), N,N-diisopropylamine (66.68 ml, 0.383 mol) and catalytic reagents [Pd(OAc)2=2.15 g, 9.57 mmol; P(O-tol)3=11.65 g, 0.0383 mol] in propionitrile (500 mL) in solution was degassed by bubbling nitrogen. The reactions were heated to 120° C. overnight. The reaction mixtures were filtered through a Celite and washed with CH2Cl2 and filtrates were combined and concentrated. The crude residue was purified by flash column chromatography eluting with 0-10% EtOAc in hexanes to afford the desired product (21.5 g). Subsequent hydrogenation in Parr shaker using Pd/C at 65 psi overnight, followed by filtration, concentration and column chromatography (0-10% ethyl acetate:hexane) afforded the desired product (17.6 g, 71%).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[OH:14].[OH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][CH:17]=1.B(O)(O)O>ClC1C=CC=CC=1Cl>[CH3:12][C:9]([C:7]1[CH:6]=[CH:5][C:4]2[O:14][C:20]([C:19]3[CH:23]=[CH:24][C:16]([OH:15])=[CH:17][CH:18]=3)=[N:2][C:3]=2[CH:8]=1)([CH3:13])[CH2:10][CH3:11]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCC(C)(C)c1ccc(O)c(N)c1
Agent: OB(O)O
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCC(C)(C)c1ccc2oc(-c3ccc(O)cc3)nc2c1
Yield: 81.5 %

Procedure:
A 350 ml three necked reaction flask, equipped with a mechanical stirrer, a thermometer a “wood metal” heating bath and a reflux condenser combined with a water separator were charged with 25.1 g (140 mmol) of 2-amino-4-(1,1-dimethyl-propyl)-phenol (see above), 19.3 g (140 mmol) of 4-hydroxy benzoic acid and 1.5 g of boric acid suspended in 140 ml of 1,2-dichlorobenzene under nitrogen atmosphere. This mixture was refluxed until two equivalents of water had separated (about 4 hours). When cold, 50 ml of diisopropylether were added and this mixture was filtered and the crystalline product was washed with diisopropylether and pentane and dried. 32.1 g (81%) of the product were obtained. M.p. 236-237° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=1)[CH:8]=[C:7]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1c[nH]c2ccc(F)cc12
Reactant: Clc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
0.384 g (12 mmol) of sodium hydride, at 75% by mass in liquid petroleum jelly, is added at a temperature in the region of 20° C. under an argon atmosphere to a solution of 2.26 g.(11.7 mmol) of 5-fluoro-3-methoxycarbonyl-1H-indole in 60 cm3 of dimethylformamide. After stirring at a temperature in the region of 40° C. for 0.5 hour, 1.98 g (12 mmol) of 4-chloroquinoline are added. After stirring at a temperature in the region of 120° C. for 6 hours, the reaction mixture is poured into 200 cm3 of water and extracted with 200 cm3 of ethyl acetate. The organic phase is washed with 3 times 100 cm3 of water and is then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 3.5 g of a brown solid which is purified by silica gel chromatography (eluent: dichloromethane). After concentrating the fractions under reduced pressure, 1.6 g of 5-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole are obtained in the form of a beige-coloured solid melting at 172° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:32]=[CH:31][N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cc(-c2ccccc2)ccn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cc(-c5ccccc5)ccn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-4-phenyl-pyridine.
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
At 0° C. to the solution of 550 mg (0.80 mmol) of Boc-Ala-Arg(Tos)-Pro-OBzl in 10 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 20:1) indicated complete disappearance of Boc-Ala-Arg(Tos)-Pro-OBzl. The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 130 mg (27%) of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6](/[CH:13]=[CH:14]/[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.BrC[C:29]([O:31][CH2:32][CH3:33])=[O:30].[CH:34]1C=CC=CC=1>[Zn]>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][C:9]([OH:12])([C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30])[C:8]2[CH:7]=[C:6](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Product: CCCOC(=O)C1(O)CCC(C)(C)c2ccc(/C=C/c3ccc(C(=O)OCC)cc3)cc21

Procedure:
To a refluxing solution of 0.75 g (11.5 mmol) of granular zinc in 5.0 mL of benzene was added a solution of ethyl (E)-4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate (Compound A2) in 5.0 mL of benzene followed by 0.27 g (0.18 mmol) of ethyl bromoacetate. The resulting mixture was refluxed for 24 h. The reaction was cooled, filtered through celite. The filtrate was washed with 10% HCl, sat. aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 10% ethyl acetate in hexane) to afford the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])=[N:5]2.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O.[OH-].[Na+]>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([NH:14][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH:16][CH:17]=1)=[N:5]2
Reactant: Nc1cccc(Oc2ccc3nccn3n2)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nccn3n2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg, 0.50 mmol) in N-methylpyrrolidone (1.0 mL) was added benzoyl chloride (0.116 mL, 1.00 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→75/25) and precipitated from ethyl acetate to give the title compound (122 mg, 74%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](O)=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].CS(Cl)(=O)=O.[N:31]1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:31])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: c1ccncc1
Reactant: CCN(Cc1cc(Cl)ccc1OCC(C)C)c1ccc(C(=O)O)nn1
Agent: CS(=O)(=O)Cl
Product: CCN(Cc1cc(Cl)ccc1OCC(C)C)c1ccc(C#N)nn1
Temperature: 4 °C
Reaction time: 1.5 h

Procedure:
6-[N-(5-Chloro-2-(2-methylpropoxy )benzyl)-N-ethylamino]pyridazine-3-carboxylic acid (example 10) (2.0 g) was dissolved in pyridine (30 ml) under argon and cooled to 4° C. Methanesulphonyl chloride (0.75 ml, 9.7 mmol) was added to the mixture which was stirred at 4° C. for 1.5 hours to give a dark purple solution. Ammonia gas was then bubbled through the solution for 2 minutes to give a dark red solution (exotherm to +15° C.) and the solution evaporated under reduced pressure. The residue was dissolved in pyridine (30 ml) and cooled under argon to 4° C. Methanesulphonyl chloride (5.1 ml, 66 mmol) was then added dropwise (exotherm to 10° C.) and the resultant brown suspension stirred at ambient temperature overnight. The brown solution was then evaporated and the residue partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with 10% 2N HCl/saturated aqueous ammonium chloride (×2), saturated aqueous sodium bicarbonate (×1) and brine (×1), dried over Na2SO4, filtered and evaporated. The title product was isolated by column chromatography using 20% ethyl acetate/isohexane as eluant (1.18 g, 62.2%). [OPPI 14: 396-9 (1982)].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12](OC(=O)C)(=[O:14])[CH3:13].P(=O)(O)(O)O>CCCCCC>[C:12]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCCCO
Agent: O=P(O)(O)O
Solvent: CCCCCC
Product: CCOC(=O)CCCCCOC(C)=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
240 g of ethyl 6-hydroxy-hexanoate are placed in a round flask which is provided with a dropping funnel, a thermometer and a stirrer. A mixture of 180 g of acetic anhydride and 3 g of 85% phosphoric acid is added dropwise thereto within a half hour while stirring. During the addition the temperature is held at 25° C. by cooling. Thereafter, the reaction mixture is heated slowly to 50° C. and held at this temperature for 3 hours. After cooling the mixture is treated with ice-water and taken up in 500 ml of hexane. The hexane solution is washed with water, with 100 ml of a 10% sodium carbonate solution and thereupon neutral with water. After drying over sodium sulphate the solvent is distilled off. 282 g of crude product are obtained. Fractional distillation gives 223 g (yield 73.7% of theory) of chemically pure ethyl 6-acetoxy-hexanoate; 190 g thereof can be used as an olfactorily pure product without further treatment.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[CH2:12]([CH2:14][NH2:15])[OH:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:15][CH2:14][CH2:12][OH:13])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: OCCNCc1cccc2cc[nH]c12
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a solution of indole-7-carboxaldehyde (10.0 g, 68.9 mmol) in 1,2-dichloroethane (300 mL) stirred under N2 at 20–24° C. was added ethanolamine (8.5 mL, 140.8 mmol), acetic acid (4.0 mL, 70.0 mmol) and NaBH(OAc)3 (16.8 g, 75.3 mmol). The resulting mixture was stirred at 20–24° C. overnight. The mixture was diluted with CH2Cl2 (200 mL), washed carefully with NaHCO3 (200 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×200 mL). The combined organic layer was washed with brine (100 mL) and dried over Na2SO4, filtered and concentrated in vacuo to give 12.4 g (95%) of the crude amine as a light yellow solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1 H), 7.41–7.39 (d, 1 H, J=7.81 Hz), 7.29 (s, 1 H), 7.0–6.99 (d, 1 H, J=6.84 Hz), 6.93–6.89 (t, 1 H, J=8.06 Hz), 6.41–6.4 (d, 1 H, J=2.44 Hz), 4.55–4.45 (bs, 1 H), 3.98 (s, 2 H), 3.49–3.47 (bt, 2 H, J=5.13 Hz), 2.61–2.58 (t, 2 H, J=5.86 Hz).
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cl-].[Zn+2].[Cl-].O1CCOCC1>[CH2:11]1[O:12][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C@@H:9]1[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: O=C1O[C@H]([C@@H]2COC(c3ccccc3)O2)C(O)=C1O
Reaction time: 1 h

Procedure:
Ascorbic acid (89.2 g.) was slurried in 400 ml. of p-dioxane, 200 g. of zinc chloride were added slowly and the resulting mixture was stirred for one hour. Next, 100 ml. (104 g.) of benzaldehyde were added. This reaction mixture was stirred at ambient temperature for about 24 hours and was then extracted with 500 ml. of ethyl acetate. The ethyl acetate extract was itself extracted with three portions of saturated aqueous sodium chloride. The ethyl acetate solution was dried and the dried solution treated with activated charcoal and then filtered through cellulose. Concentration of the filtrate caused 5,6-O-benzylidene-L-ascorbic acid to crystallize.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:11])[CH:3]=1.Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[CH2:13]([O:20][N:21]=[CH:6][C:5]1[C:4]([CH3:11])=[CH:3][C:2]([NH2:1])=[C:9]([CH3:10])[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(C=O)c(C)cc1N
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cc(C=NOCc2ccccc2)c(C)cc1N
Yield: 47.7 %

Procedure:
0.50 g (2.51 mmol) of 4-amino-2,5-dimethylbenzaldehyde is initially charged in 10 ml of methanol, 0.40 g (3.27 mmol) of O-benzyl hydroxylamine hydrochloride is added at room temperature and the reaction mixture is heated under reflux for 18 h. The mixture is then concentrated using a rotary evaporator and the residue is taken up in dichloromethane, extracted twice with water, dried over Na2SO4 and freed from the solvent under reduced pressure. This gives 0.3.8 g of product (purity 82.0%, yield 47.7%, log P (pH 2.3)=4.22).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[CH:10]3)[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([SH:36])[CH2:32][CH2:31]1)([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:24][O:25][C:26](=[O:37])[C:27]([N:30]1[CH2:31][CH2:32][CH:33]([S:36][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[CH:10]4)[C:6]=3[CH:23]=2)[CH2:34][CH2:35]1)([CH3:29])[CH3:28]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: COC(=O)C(C)(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Temperature: 120 °C
Yield: 138 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (326 mg, 0.871 mmol), 2-(4-mercaptopiperidin-1-yl)-2-methylpropionic acid methyl ester (284 mg, 1.307 mmol), Pd2(dba)3 (40 mg, 5 mol %), XantPhos (50 mg, 10 mol %) and DIPEA (0.60 mL, 3.48 mmol) in dioxane (8 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. After cooling to RT, the reaction mixture was diluted with DCM (200 mL) and purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM) affording 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester as an orange oil (614 mg, quantitative yield). LCMS: RT 2.23/2.28 min [M+H]+ 511.3.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][O:10][CH:9]=1)(=O)=O.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[O:10]1[CH:11]=[CH:12][C:8]([CH2:7][CH2:6][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[CH:9]1
Reactant: CS(=O)(=O)OCCc1ccoc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccoc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of the 2-(3-furyl)ethyl methanesulfonate in 500 ml of N,N-dimethylformamide, 14.2 g (76.8 mmol) of potassium phthalimide was added, followed by overnight stirring at 100° C. After cooling to room temperature, the reaction mixture was added to water while being stirred vigorously. The resulting precipitate was filtered, washed with water and dried to yield N-[2-(3-furyl)ethyl]phthalimide.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:8].O>C(O)(=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([N+:1]([O-:4])=[O:2])[CH:16]=2)=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Concentrated nitric acid (1.8 ml) was carefully added to a cooled suspension (5-10° C.) of phenol 27 (2.0 mg, 8.8 mmol) in 60 ml of glacial acetic acid. The reaction mixture was stirred for one hour and was then allowed to warm to room temperature and stirred for an additional 30 minutes. Water was added (50 ml) and the reaction mixture was cooled, filtered, and washed with water to yield a yellow powder. The crude product was purified via flash chromatography through a small pad of silica gel with elutions of 80/20 and 50/50 (Hex/EtOAc), respectively. Evaporation of the solvent yielded 2.23 g (93%) of a bright yellow solid.
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([NH2:18])[S:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([C:13]2[N:14]=[C:15]([NH:18][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[S:16][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cc(F)cc(C(F)(F)F)c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cc(F)cc(C(F)(F)F)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.34 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.38 g of N-[4-(3-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.