Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].[C:23]1(OC)[C:24](=[CH:27][CH:28]=[CH:29][CH:30]=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C1(C2C=CC=CC=2)C=CC(C(Cl)=O)=CC=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:4]=[CH:3][C:20]([C:23]2[CH:24]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)=[O:7]
Reactant: COc1ccccc1OC
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2ccc(-c3ccccc3)cc2)cc1OC

Procedure:
3,4-Dimethoxy-4′-phenylbenzophenone was prepared analogously to 3,4,3′,4′-tetra-methoxybenzophenone using veratrole (2.4 g, 17 mmol), aluminum chloride (2.5 g, 19 mmol) and 4-biphenylcarbonyl chloride (4 g, 18 mmol) with a reaction time of 24 hours at room temperature. The crude product was purified by flash column chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 3.86 g (70%) of the product as a white solid: mp 103–104° C.; 1H NMR (CDCl3) δ 7.88–7.84 (m, 2H), 7.73–7.64 (m, 4H), 7.52–7.40 (m, 5H), 6.93–6.90 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H); 13C NMR (CDCl3) δ 194.9, 152.9, 148.9, 144.5, 139.8, 136.8, 130.2, 130.2, 128.8, 127.9, 127.1, 126.7, 125.2, 112.0, 109.7, 55.9, 55.9; Anal. Calcd for C21H18O3. Theoretical: C, 79.23; H, 5.70. Found: C, 78.91; H, 5.87.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[C:14](C1NC=CN=1)(C1NC=CN=1)=[O:15]>ClCCl>[CH2:7]([C@H:2]1[C:3]([CH3:4])([CH3:6])[O:5][C:14](=[O:15])[NH:1]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(O)[C@@H](N)Cc1ccccc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CC1(C)OC(=O)N[C@H]1Cc1ccccc1
Yield: 95.9 %

Procedure:
To a solution of (8) (16.27 g, 90.9 mmol) in dichloromethane (1 1) was added carbonyl diimidazole (17.69 g, 109.1 mmol) and the reaction mixture was refluxed for 2 hours. The reaction was quenched with hydrochloric acid (1M) and the product extracted repeatedly with dichloromethane. The combined organic extracts were dried over magnesium sulphate. After concentration in vacuo the residue was purified by flash column chromatography using 40% ethyl acetate/40-60 petroleum ether as eluant to give the title compound (10) (17.89 g, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CC(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(C=Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1

Procedure:
A mixture of 12.25 g of the product obtained in Step 2, 1 g of para-toluenesulphonic acid and 200 ml of toluene is heated at reflux for 5 hours. After returning to ambient temperature, washing the toluene solution with a 0.1N solution of sodium hydroxide and then with water, drying over magnesium sulphate and concentration, the expected product is obtained.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[NH:18][CH2:17][CH2:16]2)[CH3:5])[CH:2]=[CH2:3].[CH2:30]=O.[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[N:18]([CH3:30])[CH2:17][CH2:16]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=O
Reactant: C=CCN(C)CCCCCCOc1ccc2c(c1)CCNC2c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)CCN(C)C2c1ccc(Br)cc1
Temperature: 65 °C

Procedure:
0.1 g of (RS)-allyl-[6-[1-(4-bromo-phenyl)-1,2,3,4-tetra-hydro-isoquinolin-6-yloxy]-hexyl]-methyl-amine (Ex. 21) is taken up in 2 ml of a 1M NaH2PO3 solution and treated with 2 ml of dioxan as a solubilizer. After the addition of 2 ml of a 37% aqueous formaldehyde solution the mixture is heated to 65° C. for 48 hrs. For the working-up, the mixture is adjusted to pH >12 with 4M aqueous sodium hydroxide solution and extracted with ethyl acetate. After evaporation of the extracts and chromatography of the residue (silica gel, toluene/acetone/triethylamine, 25:74:1) there is obtained 0.12 g of (RS)-allyl-[6-[1-(4-bromo-phenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-hexyl]-methyl-amine which is converted into its hydrochloride, MS: m/e 471 (M+H+, 1 Br).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([S:14]([CH:11]2[C:12]3[CH:13]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[CH2:8][CH2:9][CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCC2
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)C(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCC2
Reaction time: 1 h

Procedure:
7-Nitro-1-(4-trifluoromethylbenzenesulfonyl)-1,2,3,4-tetrahydronaphthalene (0.314 g, 0.816 mmol) was dissolved in ethanol (20 mL) and 10% Pd/C (50 mg) was added. Then, the reaction mixture was agitated under a hydrogen atmosphere (60 p.s.i.) for one hour using a Parr shaker. Next, the reaction mixture was filtered through Celite and concentrated to give 8-(4-trifluoromethylbenzenesulfonyl)-5,6,7,8-tetrahydronaphthalen-2-ylamine. Yield 0.30 g crude. LCMS (ESI): calc. C17H16F3NO2S=355; obs. M+H=356.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:37])[C:18]4[C:23]([C:24]=3[C:25]3[S:26][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:28][CH:29]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11](I)[C:4]=12.[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[C:43]([OH:45])[CH:44]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:13]([C:15]3[O:16][C:17](=[O:37])[C:18]4[C:23]([C:24]=3[C:25]3[S:26][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:28][CH:29]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:10]=[C:11]([C:41]3[CH:42]=[C:43]([OH:45])[CH:44]=[C:39]([F:38])[CH:40]=3)[C:4]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCCC2)s1)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCCC2)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Yield: 71.8 %

Procedure:
3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(5-(piperidin-1-ylmethyl)thiophen-2-yl)-1H-isochromen-1-one hydrochloride (Intermediate D9, 100 mg, 0.154 mmol), 3-fluoro-5-hydroxyphenylboronic acid (48.1 mg, 0.308 mmol), S-Phos-Pd-G2 (11.10 mg, 0.015 mmol) and K3PO4 (151 mg, 0.462 mmol) were reacted in THF (1.2 ml) and water (0.3 ml) under argon at 80° C. under mw irradiation for 30 min The reaction was quenched by the addition of 1M HClaqueous (2 ml) and the mixture purified via reverse phase chromatography using a Biotage C18 60 g SNAP with a gradient of water and acetonitrile to give (prior to drying a small amount of 1M HCl aqueous was added) the title compound (70 mg, 71.7% yield) as yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na]>CN(C=O)C>[CH2:11]([NH:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1nnccc1C(=O)O
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(O)c1ccnnc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1.9 %

Procedure:
3-Aminopyridazine-4-carboxylic acid (200 mg, 1.43 mmol) and benzaldehyde (0.18 mL, 1.73 mmol) were stirred in DMF (3 mL) at 90° C. for four days. The reaction mixture was allowed to cool to rt and sodium triacetoborohydride (605 mg, 2.86 mmol) was added. The reaction was stirred for 16 h. The reaction was quenched with water and extracted with EtOAc. The extracts were dried (Na2SO4) and concentrated. The residue was purified by column chromatography (0-20% MeOH/DCM). The relevant fractions were concentrated to give 6.3 mg (4%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.51 (d, 1H, 5 Hz), 7.63 (d, 1H, J=5.0 Hz), 7.30-7.39 (m, 4H), 7.22-7.25 (m, 1H), 4.72 (br s, 2H). [M+H] calc'd for C12H11N3O2, 230. found 230.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])([CH3:4])([CH3:3])[CH3:2]>[O-2].[Mn+4].[O-2].C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1C=O
Temperature: 40 °C

Procedure:
(2-Hydroxymethyl-phenyl)-carbamic acid tert-butyl ester (44.7 g, 0.200 mol), CH2Cl2 (625 mL) and manganese(IV) oxide (85%, 5 μm powder; 245.5 g, 2.400 mol) were introduced into a flask. The mixture was stirred at 40° C. for at least 4 h or until HPLC analysis showed that the reaction had proceeded to greater than 97% completion. The cooled mixture was filtered through a Celite pad (22 g) and the filter cake was rinsed with CH2Cl2 (625 mL). The filtrate and wash were concentrated in vacuo to dryness to afford the title compound as an oily yellow material (44 g, 99% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH:16]([O:18][Si:19]([CH3:29])([CH3:28])[C:20]([CH3:27])([CH3:26])[CH2:21]C(C)(C)C)[CH2:15][C:14]2=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH:16]([O:18][Si:19]([C:20]([CH3:27])([CH3:26])[CH3:21])([CH3:29])[CH3:28])[CH2:15][C:14]2=[S:42])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(S(=O)(=O)N2CC(O[Si](C)(C)C(C)(C)CC(C)(C)C)CC2=O)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(S(=O)(=O)N2CC(O[Si](C)(C)C(C)(C)C)CC2=S)cc1

Procedure:
A mixture of 3.14 g of the product obtained in Stage A above 1.55 g of Lawesson reagent in 40 cm3 of toluene is taken to reflux for 4 hours. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica (eluant: ethyl acetate - hexane 3-7). 2.45 g of desired product is obtained. M.p.=136° C. (after dissolution in ethyl acetate, filtration, evaporation to dryness, impasting in hexane).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:46]([NH:45][C:42]2[CH:43]=[CH:44][C:39]([N:38]([CH3:48])[CH3:37])=[CH:40][CH:41]=2)=[O:47])=[CH:7][N:6]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(NC(=O)Nc4ccc(N(C)C)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and 4-(dimethylamino)phenyl isocyanate using General Procedure N followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 7.99 (d, 1H), 7.95 (s, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.55 (s, 1H), 7.35 (s, 1H), 7.29 (m, 3H), 7.21 (m, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 6.70 (d, 2H), 5.39 (br, 2H), 4.04 (s, 3H), 3.92 (s, 3H), 2.83 (s, 6H); MS: (MH)+ 606.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])=[CH:15][CH:16]=1
Reactant: CCc1cnccc1C
Reactant: Clc1ccc(CCCBr)cc1
Product: CCc1cnccc1CCCCc1ccc(Cl)cc1
Yield: 56.4 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 3.53 g (15.1 mmol) of 1-bromo-3-(4-chlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.33 g of the desired compound (yield: 56.3%).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:44])[N:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35](C)(C)[O:36][SiH2]C(C)(C)C)[CH:29]=1)[CH3:26])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:44])[N:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([CH2:35][OH:36])[CH:29]=1)[CH3:26])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
TBAF (1M in THF, 2.25 mL, 2.25 mmol) was added to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-methyl-carbamic acid tert-butyl ester (450 mg, 1.13 mmol) in THF (11 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc (50 mL) was added, and the resulting mixture was washed with aq. sat. NH4Cl (2×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 40:60) yielded the title compound (110 mg, 34%). LC-MS: tR=0.91 min; ES+: 271.10.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[K+].[CH2:23]1[O:33][C:32]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][C:25]=2[O:24]1>CN(C=O)C>[CH2:23]1[O:33][C:32]2[CH:31]=[CH:30][C:27]([CH2:28][N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:8]=[C:9]5[C:14](=[CH:15][CH:16]=4)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]5)[CH2:2][CH2:3]3)=[CH:26][C:25]=2[O:24]1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(N3CCN(Cc4ccc5c(c4)OCO5)CC3)ccc2N1
Reaction time: 3.5 h
Yield: 11.9 %

Procedure:
To a mixture of 1.2 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium bicarbonate and 20 ml of DMF was added 785 mg of 3,4-methylenedioxybenzyl chloride and the mixture was stirred at 80°-90° C. for 3.5 hours. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. After washing with water the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography to give 0.2 g of 6-[4-(3,4-methylenedioxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[CH:6]1.[F:14][C:15]1[CH:16]=[C:17]([CH2:22][C:23]([NH:25][CH:26]([CH2:30][CH2:31][CH3:32])[C:27](O)=[O:28])=[O:24])[CH:18]=[C:19]([F:21])[CH:20]=1>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:27](=[O:28])[CH:26]([NH:25][C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[C:19]([F:21])[CH:20]=[C:15]([F:14])[CH:16]=2)[CH2:30][CH2:31][CH3:32])[N:7]=[CH:6]1
Reactant: COC(=O)Cn1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CC(=O)OC)cn1

Procedure:
(4-Nitro-imidazol-1-yl)-acetic acid methyl ester was reduced and coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound; MS 409.1 m/z (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH:12]1([NH:15][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(F)cc1)NC1CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 74.3 %

Procedure:
To a solution of 4-fluorophenylacetic acid (4.5 g) and cyclopropylamine (1.7 g) in N,N-dimethylformamide (60 mL) was added 1-Hydroxybenzotriazole (4.4 g), followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) hydrochloride (6.2 g) on an ice bath. This solution was stirred for 4.5 hours while gradually warming to room temperature. The reaction solution was poured into water (120 mL) on an ice bath, and the resulting solid was collected by filtration, washed with water, then dried, and the title compound (4.19 g) was obtained as a colorless solid.
Reaction SMILES: O1C2C=C3OC=CC3=CC=2CN1.COC(/C=C/C1[CH:24]=[C:23](O)[C:22]2[O:26][CH:27]([C:33]3[CH:34]=[CH:35][C:36](O)=[C:37](O)[CH:38]=3)[CH:28]([C:29](OC)=O)[C:21]=2C=1)=O.FC1C=CC=CC=1C(Cl)=O>>[C:27]([C:28]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:29]=1)(=[O:26])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)/C=C/c1cc(O)c2c(c1)C(C(=O)OC)C(c1ccc(O)c(O)c1)O2
Agent: O=C(Cl)c1ccccc1F
Agent: c1cc2cc3c(cc2o1)ONC3
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Reaction Scheme 2 proved to be useful for preparing compounds with different substituents at the 8-position of the dihydrofuro[3,2-f]-1,2-benzisoxazole nucleus. In this process, a dihydrobenzofuran intermediate (5) (prepared in Scheme 3) was subjected to a Friedel-Crafts reaction with o-fluorobenzoyl chloride to give the benzophenone intermediates (6) or (7). Use of mild reaction conditions in this acylation reaction gave the methyl ether (6) whereas more vigorous conditions led directly to the demethylated product (7). Reaction of the benzophenone (7) with hydroxylamine hydrochloride gave the corresponding oxime (8) which was converted to the oxime acetate (9) with acetic anhydride. Cyclization to (10) was achieved by treatment of the oxime acetate intermediate (9) with sodium hydride in N,N-dimethylformamide solution. The final carboxylic acid derivatives (11) were obtained from (10) by a hydrolysis reaction using potassium hydroxide in aqueous ethanol.
Reaction SMILES: CO.C[O:4][CH:5]([O:8]C)OC.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=[O:15]>C1(C)C=CC=CC=1>[CH3:18][CH:11]([CH3:12])[C:5]([OH:8])=[O:4].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=[O:15]
Reactant: COC(OC)OC
Agent: O=Cc1ccc(F)c(Br)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)C(=O)O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1.5 g of air-dried ion exchanger SPC 118 (H-form of a cation exchanger, strongly acid, macroporous), 16 g (0.5 mole) of methanol and 58.5 g (0.55 mole) of orthoformic acid trimethyl ester were added to a solution of 101.5 g (0.5 mole) of 3-bromo-4-fluorobenzaldehyde in 200 ml of toluene, the mixture was stirred for a further 1 hour without a bath and was then warmed at 50° C. for 2 hours. The reaction mixture was cooled, filtered to remove the ion exchanger and washed with 200 ml of 5% strength potassium carbonate solution. The solvent was then stripped off and the residue was distilled in vacuo. 118 g (95% of theory) of 3-bromo-4-fluorobenzaldehyde dimethyl acetate were obtained in this way, in the form of a colorless liquid with a boiling point of 68° C./0.1 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:6])=[CH:3][C:2]=1[NH:1][CH2:9][CH2:10][CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCNc1cc(C(=O)OCCCCC)ccc1OC
Temperature: 100 °C
Reaction time: 10.5 h
Yield: 133.1 %

Procedure:
3-Amino-4-methoxybenzoic acid (1.53 g, 6.45 mmol), DMF (15 ml), potassium carbonate (2.07 g, 15 mmol) and pentyl bromide (1.86 ml, 15 mmol) were mixed, and the solution was stirred at 100° C. for 10.5 hours. The reaction mixture was filtered to remove the inorganic salt, and DMF was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1) to give pentyl 4-methoxy-3-pentylaminobenzoate (1.32 g, 67%) and pentyl 3-dimethylamino-4-methoybenzoate (334 mg, 14%) as colorless oils. pentyl 4-methoxy-3-pentylaminobenzoate
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[Mg+2].[Cl-].[Cl-].[OH:13][P:14](=[O:41])([O:24][CH2:25][C@H:26]1[O:40][C@@H:30]([N:31]2[CH:37]=[C:35]([CH3:36])[C:34](=[O:38])[NH:33][C:32]2=[O:39])[CH2:29][C@@H:27]1[OH:28])[O:15]P(=O)(OP(=O)(O)O)O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>[Na+].[Cl-]>[CH3:36][C:35]1[C:34](=[O:38])[NH:33][C:32](=[O:39])[N:31]([C@@H:30]2[O:40][C@H:26]([CH2:25][O:24][P:14]([OH:15])([OH:41])=[O:13])[C@@H:27]([OH:28])[CH2:29]2)[CH:37]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O
Reaction time: 6 h

Procedure:
To 300 μl of a solution comprising 10 mM Tris-HCl (pH 7.5), 6 mM MgCl2 and 10 mM NaCl, there was added 400 μg of pCDV1 [Okayama & Berg: Mol. Cell. Biol., 3, 280 (1983)] and, after further addition of 500 units of KpnI, the reaction was carried out at 37° C. for 6 hours, whereby the plasmid was cleaved at the KpnI site. The DNA recovered byphenol-chloroform extraction followed by ethanol precipitation. About 200 μg of the KpnI-cleaved DNA was added to 200 μl of a solution prepared by adding dTTP in a concentration of 0.25 mM to TdT buffer and, after further addition of 81 units of TdT (P-L Biochemicals), the reaction was carried out at 37° C. for 11 minutes, whereby a poly(dT) chain (about 67 dT residues) was added to each 3' end of the KpnI cleavage site of pCDV1. About 100 μg of the poly(dT) chain-tailed pCDV1 DNA was recovered from the solution by ethanol precipitation following phenol-chloroform extraction. The DNA was added to 150 μl of a solution comprising 10 mM Tris-HCl (pH 7.5), 6 mM MgCl2 and 100 mM NaCl and, after further addition of 360 units of EcoRI, the reaction was carried out at 37° C. for 2 hours. The reaction mixture was treated by the LGT method, and a DNA fragment of about 3.1 kb was recovered. About 60 μg of the poly(dT) chaintailed pCDV1 was thus obtained. The DNA was dissolved in 500 μl of a solution comprising 10 mM Tris-CHl (pH 8.0) and 1mM EDTA, the solution was incubated at 65° C. for 5 minutes and then cooled with ice, and 50 μl of 5M NaCl was added. The mixture was subjected to oligo(dA)-cellulose column (Collaborative Research) chromatography. Molecules having a sufficient poly(dT) chain length were adsorbed on the column and they were eluted with a solution comprising 10 mM Tris-HCl (pH 8.0) and 1 mM EDTA to give 27 μg of the poly(dT) chain-tailed pCDV1 (hereinafter referred to as vector primer).