Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][C:12]([C:16]([O:18]C)=[O:17])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][C:12]([C:16]([OH:18])=[O:17])([CH2:11][CH2:10]1)[CH2:13][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C12CCC(NC(=O)OC(C)(C)C)(CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a solution of methyl 4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylate (2.21 g, 8.20 mmol) in THF (27 mL) and MeOH (14 mL) was added aqueous NaOH (1 N, 20.0 mL, 20.0 mmol). The mixture was stirred at room temperature for about 16 h and concentrated to dryness under reduced pressure. Water (25 mL) was added to the remaining residue and the mixture was extracted with Et2O (2×25 mL) and the Et2O extracts were discarded. The aqueous layer was acidified to about pH 4 using aqueous 6 N HCl and extracted with Et2O (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to provide 4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid as an off-white solid (1.69 g, 81%): 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.00 (s, 1H), 2.00-1.69 (m, 6H), 1.67-1.45 (m, 4H), 1.37 (s, 9H).
Reaction SMILES: [C:1]([CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])#[N:2].[ClH:10].CCCCCC.[CH3:17][OH:18]>C1(C)C=CC=CC=1>[ClH:10].[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:1](=[NH:2])[O:18][CH3:17]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CO
Agent: Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=N)CC(=O)C(C)(C)C
Reaction time: 25 h
Yield: 97.5 %

Procedure:
To a suspension of cyanopinacolone (25.034 g) in anhydrous toluene (50 ml) and anhydrous methanol (8.9 ml) is added gaseous hydrogen chloride (9.9 g) with cooling and stirring at 5° to 10° C., and the whole mixture is allowed to stand at 5° to 10° C. for 25 hours. The reaction mixture is mixed with n-hexane and the precipitated hydrochloride is filtered and washed with ethyl acetate to give methyl 4,4-dimethyl-3-oxopentanimidate hydrochloride (37.746 g) as crystals melting at 104° to 104.5° C. (decomp.). Yield is 97.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH:17]([CH3:19])[CH3:18])[CH:3]=1.Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][NH2:30])=[CH:25][CH:24]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: NOc1ccc(Cl)cc1
Reactant: CC(C)C(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)C(=NOc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 19.3 %

Procedure:
A solution of N-(4-chloro-2-isobutyrylphenyl)trifluoromethanesulfonamide 31B (244 mg, 1.11 mmol), O-(4-Chlorophenyl)hydroxylamine hydrochloride (200 mg, 0.91 mmol) and anhydrous NaOAc (91 mg, 1.11 mmol) in EtOH (10 mL) was stirred for 48 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by column chromatography (eluting with CH2Cl2/PE, 3:7) to afford N-{4-chloro-2-[1-(4-chlorophenoxyimino)-2-methylpropyl]phenyl}trifluoromethanesulfonamide 215 (80 mg, 24%), as an orange oil. 1H n.m.r. (200 MHz, CDCl3) δ 7.56, d, J=8.8 Hz, 1H; 7.45, dd, J=2.4 and 8.8 Hz, 1H; 7.27, d, J=9.0 Hz, 2H; 7.23, d, J=2.4 Hz, 1H; 7.07, d, J=9.0 Hz, 2H; 2.94, m,1H; 1.37, s, 3H; 1.19, s, 3H.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][C:7]([OH:9])=O)[CH3:3].[CH2:10]([C@H:17]1[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:21][N:20]([C:7](=[O:9])[CH2:6][CH2:5][O:4][CH2:2][CH3:3])[C@H:19]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: CCOCCC(=O)O
Agent: Cl
Product: CCOCCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 28.5 %

Procedure:
Proceeding as in Example 1, but substituting 3-ethoxypropanoic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 86, (2S,4R)-4-benzyl-1-(3-ethoxypropanoyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (8.4 mg, 28.5%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.91 (s, 1H), 7.55 (m, 2H), 7.28 (m, 2H), 7.21-7.16 (m, 7H), 6.93 (m, 2H), 4.45 (m, 1H), 3.64 (m, 1H), 3.54 (m, 2H), 3.38 (m, 2H), 3.24 (m, 1H), 2.63 (m, 5H), 1.88 (m, 2H), 1.04 (m, 3H). MS (EI) for C29H31FN2O4. found 491.6 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccc(F)c(Br)c1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(F)c(Br)c2)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 3-bromo-4-fluorophenol (0.59 g) in tetrahydrofuran (7 ml) under nitrogen was added sodium hydride, 60% dispersion in mineral oil (0.13 g). The solution was stirred at room temperature. After 30 minutes a solution of 4-methoxybenzylbromide (0.62 g) was added in tetrahydrofuran (5 ml). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was partitioned between dichloromethane and brine, then dried (MgSO4), the solvents were removed in vacuo to give a crude residue. This crude residue was purified using flash chromatography to give 2-bromo-1fluoro-4-(4-methoxy-benzyloxy)-benzene (0.71 g). To a solution of 2-bromo-1fluoro-4-(4-methoxy-benzyloxy)-benzene (0.33 g) in tetrahydrofuran (10 ml) under nitrogen was added triisopropylborate (0.29 ml). The mixture was cooled to −78° C. and 2.5M n-butyllithium solution in hexanes was added. The reaction mixture was stirred at −40° C. for 1 hour, then warmed to 20° C. and quenched with 2M hydrochloric acid (aq) (2 ml). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was adjusted to pH 7 using saturated sodium bicarbonate solution, then partitioned between ethyl acetate and water, dried (MgSO4) and the solvents removed in vacuo to yield a crude residue (0.31 g). A mixture of this crude residue and pinacol (0.25 g) in toluene (10 ml) were stirred under reflux overnight in a Dean-Stark apparatus. The solvents were removed in vacuo, the residue was then partitioned between ethyl acetate and water, the combined organics were washed with water then brine and dried (MgSO4), the solvents were removed in vacuo to yield 2-[2-fluoro-5-(4-methoxy-benzyloxy-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxyborolane (0.28 g)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[O:44]1[CH2:48][CH2:47][C@H:46]([C:49](O)=[O:50])[CH2:45]1>ClCCCl>[CH2:20]([N:17]([CH2:18][CH3:19])[C:15]([CH:14]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:49]([C@H:46]3[CH2:47][CH2:48][O:44][CH2:45]3)=[O:50])=[CH:3][C:4]=2[F:28])[CH2:9][CH2:10]1)=[O:16])[CH3:21]
Reactant: O=C(O)[C@H]1CCOC1
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCCl
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)[C@H]3CCOC3)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
A mixture of 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and DCC (1.0 mmol) in DCE (10 mL) was stirred at rt for 1 h, then was treated with (S)-tetrahydro-furan-3-carboxylic acid (1.0 mmol), and was stirred at rt for 16 h. The mixture was concentrated, and the residue was purified by PTLC to provide the title compound (74 mg, 51%). MS (ESI): mass calcd. for C27H35FN4O3, 482.27. m/z found, 483.4 [M+H]+. 1H NMR (CDCl3): 7.75-7.60 (m, 1H), 7.55-7.26 (m, 5H), 7.10-7.00 (m, 1H), 6.84 (t, J=9.0, 1H), 4.21 (s, 1H), 4.05-3.72 (m, 4H), 3.50-3.10 (m, 4H), 3.10-2.95 (m, 5H), 2.73-2.60 (m, 4H), 2.28-2.18 (m, 2H), 1.14-1.02 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][C@@H:18]([NH2:21])[CH2:19][CH3:20].CCN(C(C)C)C(C)C>CS(C)=O>[C@H:18]([NH:21][C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:19][CH3:20])[CH3:17]
Reactant: CC[C@@H](C)N
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (0.5 g, 2.1 mmol) in DMSO (10 mL) was added (R)-butan-2-amine (570 mg, 7.79 mmol) and DIEA (850 mg, 6.58 mmol). The resulting solution was stirred for 4 hours at 70° C. and then quenched by the addition of water (50 mL). The solids were collected by filtration to afford (R)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a white solid (425 mg, 75%).
Reaction SMILES: [ClH:1].C([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=2)[CH2:11]1)C1C=CC=CC=1>C(O)C.O.[Pd]>[ClH:1].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCOC(=O)COc1ccc2c(c1)CC(NCc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)COc1ccc2c(c1)CC(N)CC2
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A solution of 27 g of 2-benzylamino-7-carbethoxymethoxytetraline hydrochloride, EXAMPLE 1, in 300 ml of 95% ethanol and 25 ml of water, is hydrogenated under ordinary pressure and at temperature of 50° C. by using 3 g of 10% palladium on charcoal as a catalyst. After 3 hours, the mixture is filtered, the residue is taken up twice with 100 ml of absolute ethanol and dried every time. The product so obtained is triturated in 150 ml of acetone, filtered and crystallized from 100 ml of isopropanol to give 19 g of 2-amino-7-carbethoxymethoxytetraline hydrochloride; m.p. 143°-145° C. The product thus obtained may be used for the preparation of the compound of formula (XV) above, in which X is hydrogen and O-R' is a carbethoxymethoxy group (COMPOUND 1), as follows: A solution of 1.8 g of phenyloxirane and 3.7 g of 2-amino-7-carbethoxymethoxytetraline base, obtained by neutralization of the hydrochloride described above, in 40 ml of n-butanol is heated under reflux for 6 hours. The mixture is concentrated to dryness, the residue is purified by flash chromatography, by eluting with a mixture of ethyl acetate/methanol 9/1. The purified oil is left to react overnight with an excess of oxalic acid in 5 ml of isopropanol. Thus, 1.9 g of N-(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-2-phenylethanamine oxalate is obtained; m.p. 159°-162° C., identical with the compound of Example 5 of the European patent 211 721.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17]C)=[O:16])[N:4]=1.[OH-].[K+]>C(O)C.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH2:11][O:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([OH:17])=[O:16])[N:6]=1
Reactant: COC(=O)c1ccccc1OCc1nc(OC)cc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(COc2ccccc2C(=O)O)n1
Yield: 90.9 %

Procedure:
1.5 g of methyl 2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoate was dissolved in 10 ml of ethanol. 10 ml of water and then 7 ml of 1N aqueous potassium hydroxide solution were added to this solution, and the mixture was stirred until it got to be clear (about 4 hours). The reaction solution was diluted with water and washed with ether, the water layer was neutralized with 1N hydrochloric acid and extracted with chloroform, the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 1.3 g of 2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoic acid (yield 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.O>CC(O)=O.Br>[OH:13][C:12]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:15])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1O)C(=O)CCC2
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 10 g (0.048 mole) of 6,7-dimethoxy-1-tetralone in 100 ml of HOAc and 100 ml of 48% aqueous HBr was heated at 95° C. for 7 hours. The reaction was cooled to room temperature and poured into water and extracted with EtOAc. The EtOAc layer was dried and evaporated to 12 g of crude product. Purification on 1200 g of silica gel eluting with 10% Et2O in CH2Cl2 gave 7.5 g of product. Mp 147-148° C. (literature mp 148-152° C., Journal of Organic Chemistry, 33, 1968, p. 508).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.[C:7]1([CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CCCC)CCCC)CCC.[OH-].[Na+]>[C:7]1([C:13]2[C:14]([OH:15])=[N:6][C:3]3[N:2]([N:1]=[CH:5][N:4]=3)[C:19]=2[OH:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ncnn2c(O)c1-c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 10 g 1,2,4-triazol-3-amine and 33.7 g diethyl phenylmalonate in N,N-dibutylbutan-1-amine is stirred at 185° C. over night. The solution is diluted with 10% w/w NaOH solution, the resulting mixture is stirred for 30 min and the organic phase is separated. The aqueous layer is extracted with diethylether, acidified with concentrated HCl until precipition of the product is complete and the precipitate collected by filtration to yield the product, which is used without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2].I[CH:34]1[CH2:37][O:36][CH2:35]1.Cl.N[C@@H]1CCCC[C@H]1O.C[Si](C)(C)N[Si](C)(C)C.[Na]>[Ni](I)I>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:34]5[CH2:37][O:36][CH2:35]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)n(C(C)C)n1
Reactant: IC1COC1
Agent: I[Ni]I
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4COC4)ccc2-3)n(C(C)C)n1

Procedure:
2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-iodooxetane in a CEM microwave vial with nickel(II)iodide, trans-2-aminocyclohexanol hydrochloride and sodium hexamethyldisilazane to give 529. MS(ESI+) 383.1. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.2 Hz, 1H), 7.27 (dd, J=8.2, 1.4 Hz, 1H), 7.08 (d, J=1.3 Hz, 1H), 5.76 (hept, J=6.8 Hz, 1H), 4.94 (dd, J=8.3, 5.9 Hz, 2H), 4.63 (t, J=6.3 Hz, 2H), 4.37 (t, J=5.0 Hz, 2H), 4.31-4.20 (m, 1H), 3.43 (t, J=5.0 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][S:9]([NH:12][CH2:13][C:14](OCC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.O(C(C)(C)C)[K]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][NH:12][S:9]2(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CNS(=O)(=O)NCc1ccc(OC)cc1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CNS2(=O)=O)cc1
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of ethyl 2-((N-(p-methoxybenzyl)sulfamoyl)amino)acetate from the previous step (1.0 g, 3.47 mmol) in DMF (50 mL) was added KO-t-Bu (1.56 g, 13.88 mmol) in portions under N2 atmosphere at RT. The mixture was stirred overnight then quenched with HCl/methanol (2 M). After the solvent was removed in vacuo, the residue was washed with water to afford 2-(4-methoxy-benzyl)-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-3-one (480 mg, 54%). 1H-NMR (CDCl3): δ 7.36 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.87 (m, 1H), 4.68 (s, 2H), 4.03 (d, J=7.2 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27].[I-].[K+]>>[C:1]([C:4]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:7]([OH:8])=[CH:6][C:5]=1[O:14][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])(=[O:3])[CH3:2]
Reactant: N#CCCCCBr
Reactant: CC(=O)c1cc(C(C)=O)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(=O)c1cc(C(C)=O)c(OCCCCC#N)cc1O
Yield: 24.2 %

Procedure:
A mixture of 582 mg of 4,6-diacetylresorcinol, 460 mg of potassium carbonate, 530 mg of 5-bromopentanenitrile and 0.2 g of potassium iodide was heated at reflux overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with 40% ethyl acetate in hexane to provide 200 mg of the desired title product, m.p.=105°-106° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C.Cl>O1CCCC1>[C:18]1([C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([B:29]([OH:32])[OH:30])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2nc3ccccc3nc2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a 300 mL three-necked flask was placed 5.0 g (13 mmol) of 2-(4-bromophenyl)-3-phenylquinoxaline, and the atmosphere in the flask was replaced with nitrogen. There was added 40 mL of tetrahydrofuran, and the mixture was cooled to −78° C. under a stream of nitrogen. After cooling, 10 mL (16 mmol) of 1.6 M n-butyllithium was dripped thereinto, and the mixture was stirred at the same temperature for 1 hour. After a predetermined time, there was added 3.1 mL (27 mmol) of trimethyl borate, and the temperature of the solution was raised to room temperature, and then, the solution was stirred for 10 hours. After a predetermined time, the solution was cooled to 0° C., to which 100 mL of 0.1 M hydrochloric acid was added, and the solution was stirred for 1 hour. After a predetermined time, an organic substance was extracted with ethyl acetate from the aqueous layer. The extract was washed with a saturated aqueous sodium chloride solution together with the organic layer and then dried over magnesium sulfate. The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855). The obtained filtrate was condensed to obtain a solid. The solid was recrystallized with ethyl acetate/hexane; thus, 3.0 g of target pale-yellow powder was obtained with a yield of 66%.
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([O:22]C)=[CH:14][CH:13]=1>ClCCl>[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:3]([O:2][CH3:1])=[C:14]([CH:15]=[O:22])[CH:13]=1
Reactant: COC(Cl)Cl
Reactant: COc1ccc(F)c2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C=O)cc(F)c2ccccc12
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
5.25 mL of dichloromethyl methyl ether were dissolved in 40 mL dichloromethane and cooled to +5° C. 6.75 mL tin(IV)chloride were added neat over 45 min to the solution. After the addition the mixture was stirred for 45 min at 5° C. 11.4 g 4-fluoro-1-methoxynaphthalene in 30 mL dichloromethane was added over 1 h. Then the cooling bath was removed, and the mixture was stirred for 2 h at ambient temperature. It was then poured into ice/water. The dichloromethane layer was separated and the aqueous phase was extracted with dichloromethane. The combined dichloromethane layers were washed with water, dried over sodium sulfate, filtered through celite and concentrated in vacuo. The residue was treated with pentane to yield 9.3 g of 4-fluoro-1-methoxynaphthalene-2-carbaldehyde as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cl-].[NH+]1C=CC=CC=1.O>C(OCC)(=O)C>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[C:8]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)c1c([nH]c3cc(Br)ccc13)C2(C)C
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Yield: 101.9 %

Procedure:
3-Bromo-9-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ1, 1.50 g, 4.05 mmol) and pyridinium chloride (15.2 g, 32.5 eq.) were stirred at 160° C. for 12 hr under nitrogen atmosphere. After cooling, water and ethyl acetate were added and the resulting suspension was filtered. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting residues were washed with MTBE to obtain the title compound (brown solid, 1.47 g, 100%).
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].COCCOC.[H-].[Na+].[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]Cl>O>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:4][CH2:3][C:2]([F:12])([F:1])[C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: ClCCOCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)C(F)(F)C(F)(F)COCCOCCOC1CCCCO1
Reaction time: 1 h
Yield: 9.6 %

Procedure:
In a 2 liter-reaction vessel, 100 g (0.50M) of 2,2,3,3,4,4,4-heptafluorobutanol and 500 ml of ethylene glycol dimethyl ether were placed. To the mixture, 22 g (0.55M) of 60%-oily sodium hydride was added in 40 minutes at 10° C. or below, followed by stirring for 1 hour at the same temperature and stirring for 2.5 hours at room temperature. In a 1 liter-autoclave, the reaction mixture and 115.5 g (0.55M) of 2-chloroethoxyethyl tetrahydropyranyl ether were placed and stirred for 8 hours at 170° C. The above reaction was repeated three times, whereby 335 g in total of 2-chloroethoxyethyl tetrahydropyranyl ether was subjected to the reaction, followed by after-treatment of the reaction mixture for three times all together. More specifically, the reaction mixture for three times was poured into water all together and subjected to extraction with ethyl acetate, followed by washing with water, drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: n-hexane/isopropyl ether=1/1; 13.2 kg of 200 mesh-silica gel) to obtain 17.9 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl tetrahydropyranyl ether (purity: 99% or above) and 354 g of a low-purity product thereof.