Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C@H:5]2[C@:3]1([NH:14][S:15]([C:18]1[S:19][C:20]([C:23]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[O:25][N:24]=3)=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C@H:4]2[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[Li].O.C1C[O:38]CC1>O>[OH:7][CH2:6][C@@H:5]1[C@H:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@:3]1([NH:14][S:15]([C:18]1[S:19][C:20]([C:23]2[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[O:25][N:24]=2)=[CH:21][CH:22]=1)(=[O:16])=[O:17])[C:2]([OH:38])=[O:1]
Reactant: C1CCOC1
Reactant: O=C1OC[C@@H]2[C@H](c3ccccc3)[C@]12NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)on2)s1
Agent: [Li]O
Solvent: O
Product: O=C(O)[C@]1(NS(=O)(=O)c2ccc(-c3cc(C(F)(F)F)on3)s2)[C@H](CO)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To 5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonic acid [(1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hex-1-yl]-amide (53 mg, 11 mmol) were added LiOH—H2O (11 mg, 0.27 mmol), 1 mL of THF and 0.5 mL of water. After stirring overnight at room temperature, the reaction mixture was concentrated, diluted with water (2 mL), and acidified to pH 4 with 2N KHSO4. The product was extracted with EtOAc, washed with water (×2), brine and dried over Na2SO4. After concentrating, the product was precipitated from dichloromethane/hexane to afford the desired product as a white solid (46 mg, 86% yield).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:12]([S:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH:11]=1)C)(C)(C)C.C(OCC)(=O)C.[ClH:38].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[ClH:38].[F:21][C:17]1[CH:16]=[C:15]([C:13]2[N:12]([S:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)(=[O:23])=[O:24])[CH:11]=[C:10]([CH2:9][NH:7][CH3:6])[CH:14]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CN(Cc1cc(-c2cccc(F)c2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccc(F)c2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl{[5-(3-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (280 mg) was dissolved in ethyl acetate (3 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:ethyl acetate-hexane=1:1→9:1) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate, a 4 mol/L hydrogen chloride-ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate and hexane, and recrystallized from ethyl acetate-ethanol to give the title compound as colorless crystals (yield 84 mg, 35%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1.IC.[CH3:17]C(C)([O-])C.[K+]>>[CH3:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1
Reactant: CC(C)(C)[O-]
Reactant: c1coc(-c2n[nH]c3ccccc23)c1
Agent: [K+]
Solvent: CI
Product: Cn1nc(-c2ccco2)c2ccccc21

Procedure:
N-Methylfuranylindazole B was prepared from furanylindazole A and iodomethane in the presence of potassium t-butoxide at room temperature. Vilsmier-Haack reaction (POCl3/DMF) of furanylindazole B gave the corresponding aldehyde D which was then subjected to NaBH4 reduction to give the title compound 2.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH2:16]([NH2:18])[CH3:17].CO>>[CH2:16]([NH:18][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:17]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Solvent: CO
Product: CCNCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
Into a 100 mL round bottom flask was placed tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2 g, 9.38 mmol). To this was added 2M ethanamine in methanol (23.44 ml, 46.9 mmol). A condenser was attached to the flask and the solution was stirred at reflux (100° C.) overnight. The solution was cooled and concentrated in vacuo to afford the title compound (2.4 g) which was carried forward without further purification. MS(ES)+ m/e 259.1 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:52])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[CH:18][C:17]=1[CH2:41][O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)(C)(C)C>C(Cl)Cl>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][CH2:23][O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:13]([OH:52])=[O:12])=[C:17]([CH2:41][O:42][C:43](=[O:51])[NH:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[CH:18]=2)=[CH:32][CH:31]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (0.031 mL, 0.4 mmol) was added to a solution of 3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-2-cyclohexylcarbamoyloxymethyl-phenyl}-propionic acid tert-butyl ester (50 mg, 0.08 mmol) in CH2Cl2 (5 mL) at room temperature. The reaction mixture was stirred overnight and concentrated under vacuum to give the title compound. (39 mg, 88%). 1H-NMR (200 MHz, CDCl3): δ 7.83-7.72 (m, 4H), 7.57-7.43 (m, 3H), 7.12 (d, 1H, J=8.6), 6.98-82 (m, 4H), 5.10 (s, 2H), 4.82 (br s, 1H), 4.23 (t, 2H, J=5.9), 4.15 (t, 2H, J=5.9), 3.57-3.36 (m, 1H), 2.94 (m, 2H), 2.62 (m, 2H), 2.28 (qn, 2H, J=5.9), 1.98-1.02 (m, 10H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:27][S:26](=[O:29])(=[O:28])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:11]=3[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:40]([NH:47][CH2:48][CH2:49][CH2:50]Br)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].O>C1COCC1>[N:1]1([C:7]([C:9]2[C:10]3[CH:27]([CH2:50][CH2:49][CH2:48][NH:47][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[S:26](=[O:28])(=[O:29])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:11]=3[N:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC1c2c(C(=O)N3CCOCC3)nn(-c3ccccc3)c2-c2ccccc2S1(=O)=O

Procedure:
To a solution of 3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (150 mg; 0.37 mmol; 1 eq.) in THF (3 mL) is added potassium bis(trimethylsilyl)amide (879.19 μl; 0.5 M; 0.44 mmol; 1.2 eq.) and then 3-(boc-amino)propyl bromide (104.68 mg; 0.44 mmol; 1.20 eq.) The reaction mixture is stirred at rt for 2 days. The reaction is not complete even after addition of 2 eq. of 3-(boc-amino)propyl bromide. It is stopped by addition of water. The product is extracted with EtOAc and the combined organic phases are washed with brine, dried over MgSO4 and concentrated under reduced pressure, to afford 217 mg (quant) of the title compound. HPLC (max plot) 83.1%; Rt 4.08 min. MS (ESI−): 565.5.
Reaction SMILES: [CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14]Cl)[C:8](=[O:16])[CH2:7][C:6]=3[CH:17]=2)[O:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[CH2:28][CH:27]([NH:34][CH3:35])[CH2:26][CH2:25]2>>[CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]3[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:34]([CH3:35])[CH:27]4[CH2:26][CH2:25][C:24]5[C:29](=[CH:30][C:31]([O:32][CH3:33])=[C:22]([O:21][CH3:20])[CH:23]=5)[CH2:28]4)[C:8](=[O:16])[CH2:7][C:6]=3[CH:17]=2)[O:2]1
Reactant: O=C1Cc2cc3c(cc2CCN1CCCCl)OCO3
Reactant: CNC1CCc2cc(OC)c(OC)cc2C1
Product: COc1cc2c(cc1OC)CC(N(C)CCCN1CCc3cc4c(cc3CC1=O)OCO4)CC2

Procedure:
The title compound is prepared from 1-[7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane and 6,7-dimethoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene analogously to Example 1. Mp: 158° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[CH3:15].[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:39]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[CH3:15]
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1F
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)cn(S(=O)(=O)c2cccnc2)c1-c1ccccc1F

Procedure:
By a similar procedure as in Reference Example 256 and using 5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carbaldehyde (301 mg), sodium hydride (60% in oil, 179 mg), 15-crown-5 (0.88 mL) and pyridin-3-ylsulfonyl chloride (476 mg), the title compound was obtained as white crystals (yield 440 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH2:30]([CH2:32][NH2:33])[OH:31].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:22]([NH:33][CH2:32][CH2:30][OH:31])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCO)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (from Step 4 above) (1.9 g, 4.10 mmol) was dissolved in 20 ml of CH2Cl2. Ethanolamine (297 μl, 4.92 mmol) was added, followed, in order, by EDCI (0.764 g, 4.92 mmol), 1-hydroxybenzotriazole (0.665 g, 4.92 mmol) and triethylamine (1.14 ml, 8.20 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with NH4Cl and extracted 3 times with ethyl acetate. The combined organic layer was then washed with saturated NaHCO3 (aq.) and extracted 3 times with ethyl acetate. The organic layers were combined and washed with H2O and extracted 3 times with ethyl acetate. The organic layers were combined and dried over Na2SO4 and evaporated. The resulting residue was triturated with diethyl ether/hexane to obtain a solid, which was dried in vacuo to give a white solid (1.5 g, 72%). 1H NMR (300 MHz, CDCl3) δ 7.93 (dd, J=7.85, 1.61 Hz, 1H), 7.65 (d, J=1.61 Hz, 1H), 7.62 (app q, J=8.26 Hz, 1H), 7.40 (d, J=8.06 Hz, 1H), 7.39-7.30 (m, 1H), 7.03-6.97 (m, 1H), 6.88-6.81 (m, 1H), 6.25 (s, 1H), 5.20 (s, 2H), 3.70-3.52 (m, 1H), 3.16-3.12 (m, 2H), 2.10 (s, 3H), 1.98 (s, 3H); ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0719 (M+H calcd for C23H22BrF2N2O4 requires 507.0726).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.[F:18][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[C:6]=1[F:18]
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Product: COC(=O)Cc1cc(O)c2cc(F)ccc2c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (100 mg, 0.277 mmol) in acetonitrile (3 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (255 mg, 0.72 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, and diluted with water, then extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (30% ethyl acetate in petroleum ether) to give (1,6-difluoro-4-hydroxy-naphthalen-2-yl)acetic acid methyl ester (60 mg, 86%) as a yellow solid. MS cald. for C13H10F2O3 252, obsd. (ESI+) [(M+H)+] 253.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.02 min; [M+H]+=393.34.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[C:4]([C:9]2[N:18]=[C:17]3[C:12]([C:13]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)=[CH:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:15]1[CH:14]=[C:13]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[C:12]2[C:17](=[N:18][C:9]([C:4]3[C:3]([C:2]([F:32])([F:31])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Product: FC(F)(F)c1ccc(Nc2cc(Cl)nc3nc(-c4ncccc4C(F)(F)F)ccc23)nc1

Procedure:
Heat 7-[3-(trifluoromethyl)pyridin-2-yl]-4-{[5-(trifluoromethyl)pyridin-2-yl]amino}-[1,8]naphthyridin-2-ol (112 mg) and phosphorus oxychloride (1 mL) at reflux for 1 hour. Evaporate to dryness, partition between ethyl acetate and saturated aqueous NaHCO3 and extract with EtOAc. Dry the combined organics over Na2SO4, concentrate under vacuum to obtain the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>C1COCC1>[CH2:19]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCBr
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC1c2ccccc2-c2ccccc21
Temperature: -50 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
To a solution of fluorene (33.2 g, 0.20 mol) in 300 mL THF at −78° C., n-butyllithium (2.5 M, 80 mL) was added dropwisely. The mixture was stirred at −50° C. for 45 minutes, and then cooled to −78° C. again and n-hexylbromide (33.0 g, 0.20 mol) in THF (25 mL) was added dropwise to the mixture. The solution was allowed to warm up to room temperature and stirred for 5 h. The mixture was then poured into water and extracted with ether. The organic extracts were washed with brine and dried over magnesium sulfate, and purified by silica gel column with hexane to give pure compound 2 (38 g, yield 76%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C

Procedure:
A mixture of 75.0 g. (0.2669 mole) of 2,4-dichloro-3,5-dinitrobenzoic acid and 55.59 g. (0.2669 mole) of phosphorus pentachloride is heated at reflux for 90 minutes and cooled to room temperature. The phosphorus oxychloride is distilled off in vacuo. The residue is recrystallized from cyclohexane to yield 75.9 gm. (95%) of yellow needles melting at 99°-101°.
Reaction SMILES: CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:17]([NH:21][C:22]([C:24]1[S:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=1[C:32]([OH:34])=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([N:21]1[C:22](=[O:23])[C:24]2[S:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=2[C:32]1=[O:34])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)c1nsc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)c1nsc2c1C(=O)N(C(C)(C)C)C2=O
Yield: 95.1 %

Procedure:
7.5 g (74.1 mmol) of methylmorpholine, 2.4 g (20 mmol) of dimethylaminopyridine and 17.4 g of a 50% strength solution of propanephosphonic anhydride (27.3 mmol) in dichloromethane were added dropwise in succession to 5.4 g (20 mmol) of 5-tert-butylaminocarbonyl-3-isopropylisothiazole-4-carboxylic acid in 200 ml of dichloromethane at -5° C. and the mixture was then refluxed for 6 hours. Working up was carried out at described above for Example No. 1.003. 4.8 g (95%) of N-tert-butyl-3-isopropylisothiazole-4,5-dicarboximide were obtained as a solid of melting point 52°-53° C. (Example No. 3.001).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][O:11][C:10]=1[CH:16]([OH:25])[C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][O:11][C:10]=1[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23][CH3:24])=[CH:21][CH:22]=1)[O:25][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: CSc1ccc(C(O)c2occc(=O)c2OCc2ccccc2)cc1
Product: CSc1ccc(C(OC2CCCCO2)c2occc(=O)c2OCc2ccccc2)cc1

Procedure:
3-Benzyoxy-2-[(4-methylthiophenyl)-(tetrahydropyran-2-yoxy)-methyl]-pyran4-one: Reaction of 16.7 g of 3-benzyloxy-2-[hydroxy-(4-methylthio-phenyl)-methyl]-pyran-4-one with 3,4-dihydro-2H-pyran analogously to Example 1b yields crude 3-benzyloxy-2-[(4-methylthio-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-pyran-4-one in the form of a diastereoisomeric mixture. Rf value 0.65 (silica gel 60, hexane/dichloromethanelethyl acetate 1/1/1).
Reaction SMILES: [N+:1]([O-])(O)=[O:2].N[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:8][C:7]=1[OH:22].[Cl-].[NH4+]>O>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([C:9]([S:18]([O-:21])(=[O:20])=[O:19])=[CH:8][C:7](=[O:22])[C:6]2=[O:2])=[CH:11][CH:12]=1.[NH4+:1]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(S(=O)(=O)O)cc(O)c(N)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=O)C=C2S(=O)(=O)[O-]
Temperature: 10 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
29.6 ml (0.556 mol) of 70.4%-strength nitric acid were diluted with 82 ml of water. 80.0 g (0.298 mol) of crude 1-amino-2-hydroxy-7-methoxynaphthalene-4-sulfonic acid were added while stirring to this solution of the oxidizing agent at not more than 30° C. in the course of one hour. Stirring was continued for 1 hour, followed by cooling to 10° C., and a solution of 17.6 g of ammonium chloride in 46 ml of water was added. The suspension was cooled to 0° C. for two hours and the product filtered off by suction. The crystals were rinsed first with 25 ml of saturated ammonium chloride solution and then with 40 ml of ethanol. After drying, 77.4 g (91.3%) of crude ammonium 7-methoxy-1,2-naphthoquinone-4-sulfonate were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[NH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[C:19]1([CH2:18][CH2:17][CH2:16][NH:15][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:5]=2[C:3]([OH:4])=[O:2])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc2ccccc2c1NCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2ccccc2c1NCCCc1ccccc1

Procedure:
48 mg 1-(3-phenyl-propylamino)-naphthalene-2-carboxylic acid methyl ester were reacted with 0.14 ml of 2 M sodium hydroxide in 1 ml methanol and 1 ml of THF at 65° C. for 2 h. The organic solvents were then removed in vacuo, and the residue was taken up in water and ethyl acetate. The pH was brought to 3-4 with 2 M hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate, and concentrated. After purification by chromatography on silica (ethyl acetate/heptane) 18 mg of 1-(3-phenyl-propylamino)-naphthalene-2-carboxylic acid were obtained.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]([O:6][CH2:7][C:8](=[O:10])[CH3:9])=[C:4]([CH3:14])[CH:3]=1.[CH:15]([C:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])([CH3:17])[CH3:16]>>[CH:15]([C:18]1[CH:27]=[C:26]([C:2]2[CH:12]=[C:11]([CH3:13])[C:5]([O:6][CH2:7][C:8](=[O:10])[CH3:9])=[C:4]([CH3:14])[CH:3]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(C)C
Reactant: CC(=O)COc1c(C)cc(Br)cc1C
Product: COC(=O)c1ccc(-c2cc(C)c(OCC(C)=O)c(C)c2)cc1C(C)C

Procedure:
The title compound was prepared according to procedures analogous to those as described in Reference Example 31 by using 1-(4-bromo-2,6-dimethylphenoxy)propan-2-one and methyl 2-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C@H:10]3[CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C@H:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1.[Br-].[Al+3].[Br-].[Br-]>ClCCl>[OH:1][C:2]1[C:11]2[C@@H:10]3[CH2:12][C:13](=[O:16])[CH2:14][CH2:15][C@H:9]3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=[C:4]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@H]21
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@@H]21
Temperature: 24 °C
Reaction time: 5 h

Procedure:
To a solution of 1.0 g. of dl-cis-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one in 40 ml. of dichloromethane was added in one portion 1.0 g. of aluminum bromide. The reaction mixture was stirred for five hours at 24° C., and then was washed with 1N hydrochloric acid solution and with water. The reaction mixture was dried and the solvent was removed by evaporation under reduced pressure, thus providing dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.