Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]([F:34])([F:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>>[F:15][C:16]([F:33])([F:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Product: CCOC(=O)CCc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
In a manner directly analogous to that described in Example 8, ethyl 4-aminohydrocinnamate is alkylated with 15-(trifluoromethyl)pentadecyl bromide to form ethyl 4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamate. Subsequently, in a manner directly analogous to that described in Example 9, ethyl 4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamate is hydrolyzed to 4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamic acid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Br:28])[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Br:28])=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([CH3:17])=[N:14][C:15]=1[CH3:16])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1ccccc1Br
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1ccccc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 10 g (0.022 mol) of 4-(2-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester, obtained according A), and 80 g (0.067 mol) of pyridinium chlorochromate absorbed on alumina, was suspended on 220 ml of CH2Cl2, and the mixture was stirred at room temperature for 6 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]CCCC.[K+].[CH:37]([C:39]1[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=1)=O>O.C(OCC)(=O)C.CN(C)C=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:37]/[C:39]2[N:40]=[C:41]([NH:44][C:45](=[O:47])[CH3:46])[S:42][CH:43]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CCCC[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
A mixture of 4-nitrobenzyl bromide (6.35 g), triphenylphosphine (7.71 g) and N,N-dimethylformamide (50 ml) was stirred for 5 hours at room temperature. To the mixture were added potassium butoxide (3.96 g), and then N-(4-formyl-1,3-thiazol-2-yl)acetamide (5.0 g) prepared in a similar manner according to Step 4 of Production Example 1, and the mixture was stirred for 13 hours at the same temperature. The reaction mixture was poured into ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with 30% ethyl acetate/diisopropyl ether to give N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (7.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16][C:15]=2[N:14]=[CH:13][C:12]=1[C:27](OCC)=[O:28]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:27](=[O:28])[C:12]3=[CH:13][NH:14][C:15]4[CH2:16][CH2:17][CH:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:19][C:20]=4[C:11]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CC(c1ccccc1)CC2
Reactant: NNc1ccc(Cl)cc1
Solvent: CCCCO
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CC(c1ccccc1)CC3

Procedure:
A mixture of 1.2 g of p-chlorophenylhydrazine and 2.25 g of ethyl 4-chloro-6-phenyl-5,6,7,8-tetrahydroquinoline-3-carboxylate (Example 1e) in 100 mL of n-butanol is refluxed overnight, then evaporated to dryness. The residue is triturated with ether and filtered. Collected solid is dissolved in ethanol, decolorized with charcoal, concentrated to a smaller volume and cooled to deposit a solid, which is recrystallized from ethanol to yield 2-p-chlorophenyl-2,3,6,7,8,9-hexahydro-8-phenylpyrazolo[4,3-c]quinolin-3(5H)-one, m.p. 333°-335°.
Reaction SMILES: C([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:10]([C:11](Cl)=[O:12])[CH:9]=[C:8]2[Cl:18])CCC.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>>[Cl:18][C:8]1[C:7]2[C:15](=[CH:16][CH:17]=[CH:5][CH:6]=2)[N:14]=[C:10]([C:11]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:12])[CH:9]=1
Reactant: CCCCc1ccc2nc(C(=O)Cl)cc(Cl)c2c1
Reactant: Nc1nnn[nH]1
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1

Procedure:
In a similar manner 6-butyl-4-chloro-N-(1H-tetrazol-5-yl)quinaldamine, m.p. 275° was prepared from 6-butyl-4-chloroquinaldoyl chloride and 5-aminotetrazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:36])[C:7]2[C:8]3[C:12]([CH2:13][CH2:14][C:15]=2[CH:16]=1)=[N:11][N:10](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:9]=3)=[O:4]>Cl.CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:36])[C:7]2[C:8]3[CH:9]=[N:10][NH:11][C:12]=3[CH2:13][CH2:14][C:15]=2[CH:16]=1)=[O:4]
Reactant: COC(=O)c1cc2c(n1C)-c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1CC2
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2c(n1C)-c1cn[nH]c1CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
1-Methyl-7-trityl-1,4,5,7-tetrahydro-1,6,7-triaza-as-indacene-2-carboxylic acid methyl ester XVIII (0.74 mmol) was suspended in 3% HCl in MeOH (7 mL) and the mixture was stirred at rt for 4 h. After solvent removal the crude material was chromatographed on silica gel (eluant: AcOEt/hexane 1:1, then AcOEt and AcOEt/MeOH 4:1). Obtained the title compound in 80% yield. ESI (+) MS: m/z 232 (MH+). 1H NMR: 2.80 (m, 2H), 2.94 (m, 2H), 3.79 (s, 3H), 3.88 (s, 3H), 6.82 (s, 1H), 7.76 (s, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[C:36]1[S:40][C:39]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)[CH:31]([NH:48][C:49](=[O:79])[C:50](=[N:76][O:77][CH3:78])[C:51]1[N:52]=[C:53]([NH:56][C:57]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[S:54][CH:55]=1)[C:30]2=[O:80])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[C:36]1[S:40][C:39]([CH2:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)[CH:31]([NH:48][C:49](=[O:79])[C:50](=[N:76][O:77][CH3:78])[C:51]1[N:52]=[C:53]([NH:56][C:57]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[S:54][CH:55]=1)[C:30]2=[O:80])=[O:27])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Cc4cccnc4)s3)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A solution of m-chloroperbenzoic acid (1.46 g) in methylene chloride (30 cc) is added dropwise, in the course of 15 minutes, to a solution, cooled to 3° C., of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-[2-(pyridin-3-yl-methyl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (8.30 g) in methylene chloride (85 cc). The mixture is stirred at 3° C. for 4 hours 30 minutes and then diluted with methylene chloride (100 cc). The organic phase is washed successively with a semi-saturated solution of sodium bicarbonate (150 cc), distilled water (100 cc) and then a saturated solution of sodium chloride (100 cc). It is then dried over anhydrous sodium sulphate; the mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is purified by chromatography on a column (height=30 cm, diameter=2.5 cm) containing silica gel (0.05-0.2 mm), elution being carried out with ethyl acetate (1.2 liters) and then with a mixture of ethyl acetate and methanol (95/5 by volume) (0.8 liter) and 60 cc fractions being collected. Fractions 19 to 33, containing the pure product, are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-[2-(pyridin-3-yl-methyl)-thiazol- 5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5-oxide (5 g) in the form of a hard yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NCCCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCOc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4.5 g. of ethyl 4-{[3-(4-chlorophenoxy)propyl]amino}benzoate 4.5 g. of potassium hydroxide and 100 ml. of 95% ethanol is refluxed for 3 hours. The solution is acidified with hydrochloric acid and the mixture is diluted with 100 ml. of water to give 3.7 g. of solid. Recrystallization by dissolving in a mixture of chloroform-ethyl acetate and diluting with hexane gives 3.3 g. of product as off-white crystals, m.p. 180°-181° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].O1CCCC1.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23].Cl>C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.O.C(O)C>[CH2:22]([O:21][C:20](=[O:24])[CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:14])[CH:7]=1)=[O:13])[CH3:23]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(OC(C)C)c(C)c1
Agent: Cl
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(OC(C)C)c(C)c1
Yield: 93.6 %

Procedure:
At room temperature, to a mixture of 1-(4-isopropoxy-3-methyl-phenyl)-ethanone (described in Reference Preparation example 93) 9.4 g and tetrahydrofuran 150 ml was added diethyl carbonate 11.6 g, 55% sodium hydride 4.5 g, dibenzo-18-crown-6 0.04 g and ethanol 3 mL, and the resulting mixture was stirred with heating under reflux for nine hours. To the reaction mixture was added water, and the resulting mixture was acidified with 10% aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-isopropoxy-3-methyl-phenyl)-3-oxo-propionic acid ethyl ester 12.1 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH2:14][C:15]([CH3:17])=O)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]3[O:13][CH:14]=[C:15]([CH3:17])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)COc1cc(-c2ccc(F)cc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1coc2cc(-c3ccc(F)cc3)nn12
Temperature: 130 °C
Yield: 46.3 %

Procedure:
To a stirred solution of 1-{[3-(4-fluorophenyl)-1H-pyrazol-5-yl]oxy}acetone (0.25 g, 1.0 mmol) in toluene, equipped with dean stark apparatus, acetic acid (2 ml) and p-TsOH (25 mg, cat.) was charged at RT and the reaction mass was refluxed at 130° C. for 16 h. After completion, the reaction was diluted with EtOAc (50 ml) and washed with brine. The organic layer dried over sodium sulphate and concentrated under reduced pressure to get the crude which was then purified by column chromatography 100-200 mesh) eluted with 5-10% ethyl acetate in hexane as eluent to get compound 6-(4-fluorophenyl)-3-methylpyrazolo[5,1-b][1,3]oxazole (0.1 g, yield 43%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH:23]4[CH2:25][CH2:24]4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([CH:23]4[CH2:25][CH2:24]4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH2:6]1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCN(S(C)(=O)=O)C2)c2nc(C3CC3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
In a 10 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-yl)-amide (173 mg, 0.35 mmol) was dissolved in CH2Cl2 (1.4 mL). Trifluoroacetic acid (1.1 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (3 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (1.4 mL) and ethylenediamine (1.4 mL) was added. The reaction mixture was stirred at room temperature for 2 h then H2O and EtOAc were added. The resultant suspension was filtered, rinsing with H2O and EtOAc and dried under high vacuum to afford 103 mg (81%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-yl)-amide as an off-white solid. MS: (M+H)+=364; mp=284.0-287.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[N:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:30]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)(=[O:32])=[O:31])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)N4CCOCC4)cc3CO1)CC2
Yield: 54 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and morpholin-4-sulfonyl chloride (66 mg, 0.356 mmol) according to the procedure described for Example 27. Obtained the title compound as a light yellow foam (80 mg, 54%), MS (ISP) m/e=459.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=[O:8].I[CH2:10][CH3:11].O>C1COCC1>[CH2:10]([N:3]1[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[N:5]=[CH:4]1)[CH3:11]
Reactant: CCI
Reactant: Cc1nc[nH]c1C=O
Solvent: C1CCOC1
Solvent: O
Product: CCn1cnc(C=O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of 4-methyl-1H-imidazole-5-carbaldehyde (5.0 g, 45.4 mmol) in anhydrous THF (50 mL) was added diaza(1,3)bicyclo[5.4.0]undecane (DBU, 6.8 mL, 45.4 mmol) and iodoethane (3.4 mL, 45.4 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added before THF was evaporated. The mixture was extracted with EtOAc (1×50 mL) and 2-butanol (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-1% MeOH/DCM), affording 1-ethyl-5-methyl-1H-imidazole-4-carbaldehyde (730 mg, 12% yield).
Reaction SMILES: O1C2C=CC=CC=2C=C1C1(C(O)=O)CCC=CCN1[S:17]([C:20]1[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=1)(=O)=O.[OH:31][NH:32][C:33]([CH:35]1[CH:41]([CH2:42]OC(=O)C)[CH2:40][CH:39]=[CH:38][CH2:37][N:36]1[S:47]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)(=[O:49])=[O:48])=[O:34]>>[OH:31][NH:32][C:33]([CH:35]1[CH:41]([CH2:42][S:17][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:40][CH:39]=[CH:38][CH2:37][N:36]1[S:47]([C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)(=[O:48])=[O:49])=[O:34]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCCC2(C(=O)O)c2cc3ccccc3o2)cc1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)NO)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(CSc3ccccc3)C2C(=O)NO)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid hydroxyamide was synthesized from 3-Benzofuran-2-yl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid in the same manner as the procedures used for the preparation of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepin-3-ylmethyl ester: MS (M-H)+ =441.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:14]1([CH2:29][CH2:30][CH2:31][OH:32])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]1=2)[CH2:12][CH3:13].C(N(CC)CC)C>ClCCl>[CH2:11]([C:14]1([CH2:29][CH2:30][CH:31]=[O:32])[C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=2[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]1=2)[CH2:12][CH3:13]
Reactant: CCCC1(CCCO)c2ccccc2CCc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCC1(CCC=O)c2ccccc2CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Dissolved oxalyl chloride (1.6 mL, 2.38 g, 0.0187 mol) in 40 mL of dry dichloromethane, and cooled to -78° C. under a nitrogen atmosphere. Added dimethylsulfoxide (2.7 mL, 2.93 g, 0.0374 mol) dissolved in 10 mL of dry dichloromethane dropwise via addition funnel. Stirred for 15 mins at -78° C., and then added 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanol (4.41 g, 0.0150 mol) dissolved in 25 mL of dry dichloromethane dropwise via addition funnel. Stirred for 20 mins at -78° C., and then added triethylamine (6.3 mL, 4.55 g, 0.0449 mol). Warmed slowly to room temperature. Added water, and extracted with dichloromethane. Washed combined organic extracts with 0.5N HCl and saturated NaCl, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 3% ethyl acetate-hexane, 6% ethyl acetate-hexane, and then 10% ethyl acetate-hexane. Combined appropriate fractions, and evaporated to give 3.85 g (88% yield) of 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanal as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:19][CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])(=[O:18])=[O:17])[C:5](=[O:29])[N:4]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[C:32]([C:39](F)(F)F)[CH:31]=2)[C:3]1=[O:43].CC1(C)C(=O)N(C2C=CC([NH:58][S:59](N)(=[O:61])=[O:60])=C(C)C=2)C(=O)N1CCCCCCCCCS(CCCC(F)(F)C(F)(F)F)=O>>[CH3:44][C:2]1([CH3:1])[C:3](=[O:43])[N:4]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][S:59]([NH2:58])(=[O:61])=[O:60])=[C:32]([CH3:39])[CH:31]=2)[C:5](=[O:29])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:19][CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:24])[F:25])(=[O:18])=[O:17]
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F
Product: Cc1cc(N2C(=O)N(CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1NS(N)(=O)=O

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 3, the compound of Example 31 replacing the compound of Example 2. A colourless oil is obtained.
Reaction SMILES: [Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[CH:14]([CH3:16])[CH3:15].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([N+:17]([O-:19])=[O:18])[C:7]([OH:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)c1oc2cc(O)ccc2c(=O)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)c1oc2c([N+](=O)[O-])c(O)ccc2c(=O)c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-7-hydroxy-2-isopropyl-chromen-4-one (778 mg, 2.75 mmol) is dissolved in concentrated sulphuric acid (4 ml), and the solution is cooled to 0° C. A solution of fuming nitric acid (189 mg, 3 mmol) in concentrated sulphuric acid (1 ml) is added dropwise. The mixture is stirred at 0° C. for 30 min, poured onto ice, recovered by filtration and dried to give a cream-coloured solid.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:17][CH2:18][O:19][CH3:20])=[CH:6][C:7]([O:13][CH2:14][O:15][CH3:16])=[C:8]([CH:12]=1)[C:9](O)=[O:10])([CH3:3])[CH3:2].C(Br)C1C=CC=CC=1.O.[NH2:30][NH2:31]>O1CCCC1>[CH:1]([C:4]1[C:5]([O:17][CH2:18][O:19][CH3:20])=[CH:6][C:7]([O:13][CH2:14][O:15][CH3:16])=[C:8]([CH:12]=1)[C:9]([NH:30][NH2:31])=[O:10])([CH3:3])[CH3:2]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)O
Reactant: NN
Agent: BrCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cc(OCOC)c(C(C)C)cc1C(=O)NN
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
5-isopropyl-2,4-bis-methoxymethoxy-benzoic acid (IM3-a: 2.84 g, 10 mmol), N,N′-carbonyldiimidazole (1.62 g, 10 mmol) and tetrahydrofuran 100 mL were placed in a 300 mL eggplant shaped flask and stirred at room temperature for 4 hours. The reaction mixture was mixed with benzylbromide (1.19 mL, 10 mL), stirred at room temperature for further 4 hours and then mixed with hydrazine mono hydrate (0.63 mL, 13 mmol) and stirred at room temperature overnight. After completing the reaction, most of the reaction mixture was removed under reduced pressure, and the residue was mixed with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate and saturated sodium chloride solutions, dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was purified by silica gel column chromatography to obtain the title compound (IM4-a: 2.44 g, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:8]=[N:7][CH:6]=1)[CH3:2].Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].[CH2:32]([Mg]Br)[CH3:33]>C1COCC1>[C:26]1([O:25][C:23]([N:7]2[CH:8]=[C:9]([O:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH:10]([CH2:32][CH3:33])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:21])=[CH:6]2)=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cncc(OCCc2cccc(Cl)c2)c1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)C1=CN(C(=O)Oc2ccccc2)C=C(OCCc2cccc(Cl)c2)C1CC
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
The compound of step 1 (100 mg, 0.327 mmol) was dissolved in THF (1.5 ml) and the mixture was cooled to −30° C. Phenyl chloroformate (77.6 mg, 0.49 mmol) was added and the mixture was stirred for 10 minutes. Ethyl magnesiumbromide (0.589 ml, 1M in THF) was added at −30° C. and the mixture was stirred for 30 minutes, partitioned between diethylether and aqueous ammonium chloride solution, the combined organic extracts were dried over sodium chloride and evaporated to dryness in vacuo. The raw material was purified by silica gel chromatography with a heptane/ethyl acetate gradient to yield the title compound (84 mg).