Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[C:3](=[O:13])[CH:4]([CH:10]([CH3:12])[CH3:11])[C:5]([O:7][CH2:8]C)=[O:6].Br>>[OH:13][C:3]1[CH2:8][O:7][C:5](=[O:6])[C:4]=1[CH:10]([CH3:11])[CH3:12]
Reactant: CCOC(=O)C(C(=O)CBr)C(C)C
Agent: Br
Product: CC(C)C1=C(O)COC1=O
Temperature: 100 °C

Procedure:
A mixture of ethyl 4-bromo-2-isopropyl-3-oxobutanoate (7.1 g, 28 mmol) and hydrogen bromide (48%, 0.032 mL, 0.28 mmol) was heated at 100° C. for 8 h. After cooling to rt, the solid was collected by filtration followed by diethyl ether washing to give 4-hydroxy-3-isopropylfuran-2(5H)-one. LCMS: (M+1)+:143.09.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[C:29]1(O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[F:28][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]([O:27][C:37]4[C:38]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:34]=[CH:35][CH:36]=4)=[O:26])[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=C(O)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reactant: Oc1cccc2ccccc12
Product: O=C(Oc1cccc2ccccc12)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1

Procedure:
2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1, 7.00 g) is reacted analogously to Example I-811 with 1-naphthol (3.12 g). This gives, after chromatographic purification, 1-naphthyl-2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (4.0 g, 44%).
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@@H:5]([CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)[CH2:4][O:3]1>C(O)(C(F)(F)F)=O.O>[NH2:6][C@@H:5]([CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][O:17][CH2:16]1)[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCCOC2)COC1(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CO)C[C@H]1CCCOC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 293.8 %

Procedure:
(S)-tert-butyl 2,2-dimethyl-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)oxazolidine-3-carboxylate (32 g) was dissolved in a mixture of TFA (160 mL) and water (160 mL). The mixture was stirred at room temperature for 10 min. The mixture was then concentrated in vacuo to give the crude product (50 g), which was used for the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cn1c(=O)ccc2ncccc21
Product: O=C(Cn1c(=O)ccc2ncccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (42 mg, 0.204 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.101 mmol) according to protocol A. Retention time (min)=2.295, method [7], MS (ESI) 431.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.57 (dd, J=4.6, 1.7 Hz, 1H), 8.16 (d, J=9.9 Hz, 1H), 8.11 (s, 1H), 7.98 (d, J=9.1 Hz, 1H), 7.62 (dd, J=8.8, 5.1 Hz, 1H), 7.01 (d, J=4.3 Hz, 1H), 7.05 (s, 1H), 5.33 (s, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11](Cl)=[O:12].[CH2:14]([O:16][C:17]([C@@:19]1([CH3:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1)=[O:18])[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:14]([O:16][C:17]([C@@:19]1([CH3:25])[CH2:24][CH2:23][CH2:22][N:21]([C:11]([C@@H:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)=[O:12])[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)[C@@]1(C)CCCNC1
Reactant: O=C(Cl)[C@H]1COc2ccccc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@@]1(C)CCCN(C(=O)[C@H]2COc3ccccc3O2)C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxine-2-carbonyl chloride (6.05 g, 30.5 mmol) in DCM (20 ml) was added to a stirred mixture of (S)-3-methyl-piperidine-3-carboxylic acid ethyl ester (5.0 g, 29.2 mmol), DIPEA (5.5 ml, 31.7 mmol) and DCM (30 ml), previously cooled down to 5° C. The cooling bath was removed and stirring continued at RT for 1 h. The reaction mixture was washed twice with 1 M HCl, twice with sat. aq NaHCO3 and twice with water and dried with Na2SO4. Solvent was evaporated to give 9.66 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:24])[C:20]=1[N:21]([CH3:23])[CH3:22])[CH:16]=[O:17]>O1CCOCC1>[CH3:23][N:21]([CH3:22])[C:20]1[C:19]([CH3:24])=[CH:18][C:15]([CH:16]2[O:17][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:14][C:13]=1[CH3:12]
Reactant: Cc1cc(C=O)cc(C)c1N(C)C
Reactant: CC1(C)N=C1c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C2OC(C)(C)N=C2c2ccccc2)cc(C)c1N(C)C

Procedure:
2.6 g of 2,2-dimethyl-3-phenyl-2H-azirine and 2,5 g of 3,5-dimethyl-4-(dimethylamino)benzaldehyde were exposed to light for 2 hours in 300 ml of 1,4-dioxane (with the light source described in Example 2). After purification as described in Example 12 and crystallization from n-pentane, there was obtained 5-[4(dimethylamino)-3,5-xylyl]-2,2-dimethyl-4-phenyl-3-oxazoline which melted at 91°-92° C. after drying for 2 hours at 50° C. and 13 Torr.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Sn](Cl)(Cl)(Cl)Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][C:23]=1[C:30]#[N:31]>C(O)(=O)C>[C:30]([C:23]1[CH:24]=[C:25]([N:28]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:29]2)[CH:26]=[CH:27][C:22]=1[F:21])#[N:31]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccco1
Reactant: N#Cc1cc(NN)ccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccco2)n(-c2ccc(F)c(C#N)c2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To ethyl 4-(2-furyl)-2,4-dioxobutyrate (3.5 g, 16.7 mmol) in 50 mL of glacial acetic acid was added 4-fluoro-3-cyanophenylhydrazine tin chloride (6.3 g, 16.7 mmol). The reaction was stirred at 100° C. for 4 h. The reaction was allowed to cool to room temperature and the acetic acid was removed in vacuo. The residue was diluted with ethyl acetate and the organics were washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by recrystallization from hexane/ethyl acetate to afford 2.5 g (46%) of the title compound. LRMS (ES+): 326.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:18][CH3:19].O>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:18]([O:14][CH:11]1[CH2:10][CH2:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12]1)[CH3:19]
Reactant: CCBr
Reactant: OC1CCC(c2cccc(F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1CCC(c2cccc(F)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
The compound (20) (40.9 g), sodium hydride (11.2 g) and dimethylformamide (200 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 60° C. The mixture was stirred for 1 hour, then bromoethane (21) (25.2 g) dissolved in dimethylformamide (250 ml) was added dropwise thereto, and the mixture was heated to 120° C. The stirring was continued for 2 hours, and cooled slowly to room temperature, and then water (500 ml) and toluene (500 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with water and a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and then the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=25:1 by volume) as an eluent and silica gel as a stationary phase powder and dried, giving 43.2 g of 1-(4-ethoxycyclohexyl)-3-fluorobenzene (22). The yield based on the compound (20) was 92.3%.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1>CN(C=O)C.O>[CH:1]1([O:5][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[CH:15][C:14]=3[CH:18]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCC1
Reactant: BrCc1ccc2occc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc2cc(COC3CCC3)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of cyclobutanol (1.0 mL, 14.0 mmol) and sodium hydride (0.5 g, 14.0 mmol) in DMF (20 mL) was stirred at 0° C. for 30 minutes. 5-(Bromomethyl)benzofuran (2.9 g, 14.0 mmol) was the added and resultant reaction mixture was slowly warmed to room temperature and left stirring over night. Reaction mixture was diluted to 100 mL with water. The solution was extracted with Et2O (20 mL×3); the combined extracts were washed with 1N NaOH solution, water and brine, dried, and concentrated under reduced pressure to yield the desired product after purification on silica (4/1 hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 2H), 7.42 (d, 1H), 7.27 (d, 1H), 6.78 (s, 1H), 4.54 (s, 2H) 4.03 (m, 1H), 2.21 (m, 2H), 1.94 (m, 2H), 1.76 (m, 1H), 1.52 (m, 1H).
Reaction SMILES: C([O-])(=[O:8])C1C=CC=CC=1.[CH2:10]([P+:14]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13].C(O)(=O)C1C=CC=CC=1>>[OH-:8].[CH2:23]([P+:14]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH3:26]
Reactant: O=C([O-])c1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C(O)c1ccccc1
Product: [OH-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Tetrabutylphosphonium benzoate is also prepared in the following way. A solution of tetrabutylphosphonium hydroxide (4.7 g; 40% in water) is prepared. Then benzoic acid (0.8 g) is added, and the reaction solution is stirred at room temperature for 5 hours. The water is then removed in a rotary evaporator, and the residue is taken up in toluene. The toluene is removed in a rotary evaporator, and the residue is again taken up in toluene. This procedure is repeated 4-5 times. The solvent is then removed to dryness.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[F:8][C:9]([F:32])([F:31])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[CH:29]\O)/[C:25]([O:27][CH3:28])=[O:26])[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:31][C:9]([F:8])([F:32])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[CH:29]\[O:6][CH3:7])/[C:25]([O:27][CH3:28])=[O:26])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)/C(=C/O)c1ccccc1COc1cccc(C(F)(F)F)n1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dimethyl sulphate (0.65 ml, 6.9 mmol) was added dropwise to a mixture of (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (2.12 g, 6 mmol) and anhydrous potassium carbonate (1.2 g, 8.7 mmol) in dry DMF (10 ml). After stirring at room temperature for 6 hours, the mixture was poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and concentrated to give a crude product which was purified by column chromatography (silica eluted with 20% ethyl acetate in hexane) to give (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-methoxyacrylate (Compound No.177 in Table I of EP-A-0278595); (1.01 g, 46%) as a cream solid; mp 73-74° C.; 1H NMR (270 MHz)δ: 3.68(3H,s), 3.82(3H,s), 5.34(2H,s), 6.87(1H,d), 7.15-7.70(6H,m), 7.55(1H,s) ppm.
Reaction SMILES: [F:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].Cl>C1COCC1.CCOC(C)=O>[Cl:10][C:9]1[C:2]([F:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH2:4][NH:5][C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: NCc1cccc(Cl)c1F
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(=O)NCc1cccc(Cl)c1F
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-3-chlorobenzylamine (1 g, 6.27 mmol) and TEA (1.05 mL, 7.52 mmol) in THF (20.9 mL) was added acryloyl chloride (0.61 mL, 7.52 mmol) dropwise and the reaction mixture was stirred at 23° C. for 2 h. The reaction mixture was diluted in EtOAc, HCl 1N was added and the layers separated. The aqueous layer was extracted again with EtOAc and the combined organic layers were dried, filtered and concentrated to dryness. The crude residue was purified by flash column chromatography on silica gel (xyclohexane/EtOAc gradient 100:0 to 1:1) to give the desired material. TLC, Rf (c-hexane/EtOAc 5:5)=0.41; MS (LC/MS): 214.0 [M+H]+; tR (HPLC conditions b): 3.35 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:16]1(C)C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCOCC>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:14][CH3:15])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1]
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a round bottom flask, 2-fluoro-5-methoxy-4-nitro-benzoic acid (2.84 g, 0.0132 mol;), toluene (25 mL, 0.23 mol), methanol (5 mL, 0.1 mol;) were added. 2.00 M of trimethylsilyldiazomethane in ether (7.92 mL) was added drop wise at 5° C. The reaction was stirred at room temperature for 2 hours. The solvent was removed under vacuum to afford a yellow solid. The solid was triturated with 10% Et2O and hexane to give 2-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester as an off white solid (2.84, 93%). 1H-NMR (DMSO-D6, 400 MHz): δ 8.06 (d, 1H), 7.70 (d, 1H). 4.14 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1=[CH:3][CH2:4][CH2:5][C:6]([CH:8]=[CH:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:12]1)=[CH2:7]>CCCCCC>[CH3:14][CH:13]([C@H:10]1[C@@H:11]2[C@H:12]3[C:2](=[CH2:1])[CH2:3][CH2:4][C@H:5]3[C@:6]2([CH3:7])[CH2:8][CH2:9]1)[CH3:15]
Reactant: C=C1C=C[C@H](C(C)C)CCC(C)=CCC1
Agent: C=C1/C=C/[C@H](C(C)C)CC/C(C)=C/CC1
Solvent: CCCCCC
Product: C=C1CC[C@@H]2[C@H]1[C@H]1[C@H](C(C)C)CC[C@]12C
Yield: 92.9 %

Procedure:
100 g of the essential oil of Solidago altissima L. was distilled under reduced pressure and 14 g of germacrene D was obtained. 14 g of the germacrene D was dissolved in 2.6 l of n-hexane and the solution thus obtained was subjected to internal irradiation with the light of low pressure mercury lamp for 190 hours. 13 g of β-bourbonene was obtained. In the case of the irradiation with the light of high pressure mercury lamp the similar result was obtained. (Note: The above-mentioned irradiation time is for 14 g of germacrene D. If irradiation is to be given to 100 g of essential oil containing 40 g of germacrene D, irradiation time required will be about 540 hours.)
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:12](O)(=[O:16])[C:13]([CH3:15])=O.Cl>C(O)(=O)C>[CH2:1]([CH:5]1[CH:6]=[C:7]2[O:11][C:12](=[O:16])[C:13]([CH3:15])=[C:8]2[CH2:9][CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)C(=O)O
Reactant: CC(C)CC1CCCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Product: CC1=C2CCC(CC(C)C)C=C2OC1=O

Procedure:
The process according to claim 1, wherein 3-isobutyl-cyclohexanone and pyruvic acid are heated in an HCl and acetic acid solution to give 6-isobutyl-3-methyl-2,4,5,6-tetrahydro-benzo[b]-furan-2-one and this product is heated for 4 to 5 hours with pyridine hydrochloride to give p-isobutylhydratropic acid.
Reaction SMILES: CC([N:5]([C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[S:27])[C@H:6]([C:23]([OH:25])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=1)(C)C.BrC1C=CC2N=C(N[C@H](C(O)=O)[CH2:46][C:47]3[CH:52]=CC(OCCCC(=O)NC4NCCCN=4)=C[CH:48]=3)SC=2C=1>ClC1C=CC=CC=1.C(OCC)(=O)C>[Br:35][C:32]1[CH:31]=[CH:30][C:29]2[N:28]=[C:26]([NH:5][C@H:6]([C:23]([O:25][C:47]([CH3:52])([CH3:48])[CH3:46])=[O:24])[CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=3)[S:27][C:34]=2[CH:33]=1
Reactant: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)O)cc1)NC1=NCCCN1
Reactant: CCOC(=O)CCCOc1ccc(C[C@@H](C(=O)O)N(C(=S)Nc2ccc(Br)cc2)C(C)(C)C)cc1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 19.9 %

Procedure:
0.6 ml of SO2Cl2 in 5 ml of chlorobenzene is added to a solution of amino thiourea 8-1 (3 g, 5.3 mmol) in 60 ml of chlorobenzene at 0° C., agitation is carried out for 2 hours at ambient temperature, followed by diluting in ethyl acetate, washing, drying and evaporating the organic phase under reduced pressure, in order to obtain the crude product which is purified by chromatography eluting with a heptane/ethyl acetate mixture 80/20. 593 mg of expected product is obtained 8-2.
Reaction SMILES: N([CH:4]([NH2:13])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[F:12])=[N+]=[N-].[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1>[F:12][C:6]1[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:5]=1[CH:4]([NH2:13])[CH3:14]
Reactant: [N-]=[N+]=NC(N)c1ccc(Br)cc1F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(N)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To C-Azido-C-(2-fluoro-4-bromo-phenyl)-methylamine (0.35 g, 1.43 mmol) was added triphenyl phospine (0.45 g, 1.72 mmol), 2N HCl (2 mL), and THF (2 mL). The reaction mixture was stirred at r.t. for 2 h and the reaction quenched with NaHCO3 (10 mL) and pH adjusted to 8, extracted with dichloromethane (2×30 mL) and washed with brine. The combined organic phases were dried over Na2SO4, filtered and evaporated yielding the crude product. Purification by chromatography (silica, EtOAc/Heptane, 1:1, followed by CH—2Cl2/MeOH 9:1 and with addition of a SCX colon) yielded 93 mg (30%) of 1-(2-Fluoro-4-bromo-phenyl)-ethylamine. 1H NMR δ (CDCl3): 1.44 (3H, d), 2.48 (2H, br s), 4.41 (1H, q), 7.19-7.40 (3H, m).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[C:14]([Cl:21])=[CH:13][CH:12]=1>>[Br:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[C:14]([Cl:21])=[C:13]([N+:1]([O-:4])=[O:2])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1nc(Br)ccc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc(Br)cc([N+](=O)[O-])c1Cl
Temperature: 70 °C

Procedure:
To a solution of fuming nitric acid (10 mL) and fuming sulfuric acid (10 mL) was added methyl 6-bromo-3-chloropyridine-2-carboxylate, N-oxide and the reaction was heated to 70° C. in an oil bath for 4 hr. The mixture was poured over ice water (100 mL) and extracted with ethyl acetate (3×75 mL) and the combined extracts were backwashed with brine, dried (Na2SO4) and concentrated. The dark oil was chromatographed over silica in 4:1 EtOAc/hexane to give methyl 6-bromo-3-chloro-4-nitropyridine-2-carboxylate, N-oxide (0.007 mol, 2.2 g). 1H NMR (CDCl3): δ 4.1 (3H, s), 8.4 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH:28]([Sn](CCCC)(CCCC)CCCC)=[CH2:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([CH:28]=[CH2:29])[CH:3]=3)[S:9][C:10]=2[C:16]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C=Cc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1
Temperature: 100 °C
Yield: 56.2 %

Procedure:
To a stirred solution of 200 mg (0.45 mmol) 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide in 10 ml DMF were added 283 mg (0.89 mmol) vinyltri-n-butyltin, 38 mg (0.05 mmol) bis(triphenylphosphine)palladium(II) chloride, 70 mg (0.27 mmol) triphenylphosphine, 151 mg (3.57 mmol) lithium chloride and 10 mg (0.04 mmol) 2,6-di-tert-butyl-para-cresol. The mixture was heated at 100° C. for 48 h and then poured onto water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (hexane then 1/1 ethyl acetate/hexane) followed by trituration in hexane/dichloromethane afforded 100 mg (57%) N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-vinyl-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 396 (M+H+, 100).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([CH3:6])(=[O:9])=[O:8])=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)Cl
Product: CS(=O)(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To 300 ml (4.53 mol) of chlorosulfonic acid was added 300 g (1.57 mol) of 4-methanesulfonylchlorobenzene at room temperature while stirring. The mixture was heated to 120° C., at which stirring was continued for 16 hours. After cooling, the reaction mixture was poured into ice-water, and the resulting crystals were collected by filtration and air-dried to obtain 293 g (yield: 64%) of HD-39a.
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: O
Solvent: ClC(Cl)(Cl)Cl
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.