Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=[CH:23][C:15]1=2)C(=O)OC1C=CC=CC=1>C(O)C.O.[OH-].[Na+]>[CH3:1][NH:2][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[C:21]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])[CH:22]=[CH:23][C:15]1=2
Reactant: CN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNCCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 78 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of phenyl methyl(2-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (65 mg, 0.144 mmol) in ethanol (4 mL) was added sodium hydroxide (57.4 mg, 1.436 mmol) as a solution in water (2 mL). The resulting mixture was heated to 78° C. and stirred overnight. The mixture was then cooled to room temperature, diluted with water and sodium hydroxide, and extracted with dichloromethane (5×). The combined organics were dried, filtered, concentrated, and then chromatographed in 10% (2M NH3 in MeOH) in dichloromethane, giving the desired product (22 mg, 46%). 1H NMR (DMSO-d6) δ 7.69 (d, J=3.3 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H), 7.07 (t, J=4.4 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.53-6.44 (m, 2H), 6.29 (brs, 2H), 3.54-3.51 (m, 2H), 3.3 (m, 2H), 3.04-3.00 (m, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.32 (s, 3H); MS-EI: (m/z, %) 332 (M+, 75), 288 (97), 260 (100); EI-HRMS calculated for C16H20N4S2 (M+), calculated: 332.1129, observed: 332.1145. HPLC: 95% by area.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[N:27]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:28][C:26]1[N:27]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)c1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
A mixture of 197b (500 mg, 1.8 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (530 mg, 2.0 mmol), N-ethyl-N-isopropylpropan-2-amine (1.5 mL, 0.90 mmol), and propan-2-ol (20 mL) was stirred at 100° C. for 15 h. After the reaction was completed, the solvent was removed under reduced pressure to afford 197c as a brown solid (375 mg, 45%). MS-ESI: [M+H]+ 465.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:6][CH:5]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C1(C2[N:41]([CH2:42][CH2:43][O:44][CH2:45][CH3:46])[CH2:40][CH:39]([CH2:47]O)[O:38]2)C=CC=CC=1>CN(C=O)C.O>[NH3:11].[CH2:45]([O:44][CH2:43][CH2:42][NH:41][CH2:40][CH:39]([OH:38])[CH2:47][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:11][CH:12]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1)[CH3:46]
Reactant: Oc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Reactant: CCOCCN1CC(CO)OC1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCNCC(O)COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1
Product: N
Temperature: 70 °C
Reaction time: 18 h
Yield: 13.8 %

Procedure:
Under N2, NaH (60% oil dispersion, 1 g, 0.025 mol) was added to DMF (20 ml) and heated at 70° C. while a solution of 2-(4-hydroxyphenyl)-4-(2-thienyl)imidazole (5.0 g, 0.021 mol) in DMF (40 ml) was added dropwise. After heating at 70° C. for 0.5 hours, a solution of the tosylate of 2 (0.022 mol) in DMF (25 ml) was added dropwise and the mixture heated at 110° C. After 18 hours, the reaction mixture was poured into H2O and the suspension extracted with EtOAc (4X). The organic extracts were washed with H2O, saturated NaCl, dried, filtered and concentrated to dryness. The residue was treated with AcOH (25 ml) and H2O (175 ml) and the mixture stirred at room temperature. After 18 hours, the aqueous layer was extracted with Et2O (2X), adjusted to ph>10 with saturated Na2CO3 and extracted with CHCl3 (3X). The CHCl3 extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel eluting with 5% CH3OH--CHCl3 saturated with NH3 to yield 0.56 g (6.6%) of 3; m.p. 144°-6° C. (CH3CN).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=O)C(C)(C)C)C(=O)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[CH2:31]=[O:32]>C(O)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]2[N:12]([CH2:13][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:31](=[O:32])[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: C=O
Solvent: CCO
Product: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1CN1CCCC1

Procedure:
A mixture of 500 mg (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H), 329 μl pyrrolidine and 415 μl formaldehyde in 3.5 ml ethanol were heated at reflux for 3 h. A further quantity of 164 μl pyrrolidine and 148 μl formaldehyde were added and the mixture refluxed for about 24 h. The mixture was concentrated to dryness and purified by chromatography to obtain 533 mg of (S)-5-biphenyl-4-ylmethyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one (1-a, R1=methylpyrrolidin). 1H NMR (DMSO): 1.69 (4H, m, 2×NCH2CH2); 1.68-2.15 (4H, m, 3-CH2, 4-CH2); 2.50 (4H, 2×NCH2); 2.66 (1H, dd, 1-CHH); 3.12 (1H, dd, 1-CHH); 3.94 (1H, d, NCHHN); 4.21 (1H, d, NCHHN); 7.29 (2H, d, aromatic); 7.33 (1H, t, aromatic); 7.44 (2H, t, aromatic); 7.59 (2H, d, aromatic); 7.64 (2H, d, aromatic). m/z: 335 (MH+, 100%)
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH:13]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:10][C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:32][O+](C)C>>[C:1]1([N:7]2[C:11]([CH2:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:32])=[N:19]3)=[CH:10][C:9]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCCC(Cc2cc(-c3ccccc3)nn2-c2ccccc2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2cc(-c3ccccc3)nn2-c2ccccc2)CCCC1

Procedure:
The title product of Example 146 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [C:1]1([C:7](=[O:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:12].[Na+].[CH2:14]([Sn:18](Cl)(Cl)[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>O.C1COCC1>[C:1]1([C:7](=[O:11])[C:8]([O:9][Sn:18]([O:9][C:8](=[O:10])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Reactant: O=C(O)C(=O)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(OC(=O)C(=O)c1ccccc1)OC(=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
In a 50 ml dry three-neck-flask, 4.9 g (33.0 mmol) of phenylglyoxylic acid are dissolved under nitrogen in solution, of 1.45 g (36.3 mmol) of NaOH in 6 ml water at 0° C. 5.0 g (16.5 mmol) dibutyltin dichloride in 15 ml THF are added dropwise in the course of 0.5 h at 0° C. The emulsion is slowly warmed to room temperature, then heated to 40° C. and stirred for 30 min. The formed oil is separated off and the aqueous phase is extracted several times with methylene chloride. The oil and the methylene chloride phases are combined, dried over MgSO4, filtered and concentrated. The resulting oil is dissolved with heating in 20 ml of pentane and 10 ml of toluene and cooled. The crystals are filtered off at 0° C., dissolved in 20 ml of acetonitrile and extracted with 10 ml of heptane. The acetonitrile solution is concentrated affording 2.6 g of the title product as a yellow oil, which is recrystallized from 10 ml of pentane and 4 ml of ortho-xylene. The white crystals melt at 82-84° C. The structure of the product is further confirmed by 1H-NMR- and 13C-NMR-spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=1[CH2:18][NH:19][C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C(O)CO>C(O)(C)C.[Cu](I)I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:22]2[CH2:23][CH2:24][CH:20]([NH:19][CH2:18][C:17]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:16]=3[Cl:15])[CH2:21]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)cn1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Clc1ccc(CNC2CCN(c3ccc(Cl)nc3)C2)c(Cl)c1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
Add 2-chloro-5-iodopyridine (193 mg, 0.84 mmol) to a mixture of potassium carbonate (344 mg, 1.61 mmol) and copper iodide (7 mg, 5% mol) and purge with nitrogen for 10 min. Add a solution of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (238 mg, 0.97 mmol) in ethylene glycol (0.09 mL, 1.61 mmol) and isopropanol (1 mL). Stir at 80° C. for 4 days. Add water (2 mL) and extract with ethyl acetate, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and chromatograph using preparative mass guided chromatography to give the title compound. Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (400 MHz, MeOH-d4) δ 7.79 (1H, d, J=2.69 Hz), 7.63-7.70 (2H, m), 7.49 (1H, dd, J=8.31, 1.96 Hz), 7.34 (1H, d, J=8.80 Hz), 7.21 (1H, dd, J=8.80, 2.93 Hz), 4.48 (2H, s), 4.17-4.24 (1H, m), 3.72-3.79 (1H, m), 3.61-3.68 (2H, m), 3.38-3.44 (1H, m), 2.59-2.69 (1H, m), 2.32-2.33 (1H, m), 2.32-2.40 (1H, m), MS (ES): m/z=356 [M+].
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[N:7][C:6]=2[C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:13])=[C:6]2[C:10]=1[O:9][C:8]([CH3:11])=[N:7]2
Reactant: Cc1nc2c(CO)ccc(Br)c2o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc2c(C=O)ccc(Br)c2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of (7-bromo-2-methyl-benzo[d]oxazol-4-yl) methanol (5.16 g) in dichloromethane (300 ml) was added manganese(IV) oxide (59.9 g) and the suspension stirred at ambient temperature for 16 hours. The reaction mixture was filtered through a plug of silica gel and the filtrate concentrated to give 7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde (3.23 g). LC-MS: RT=1.83 min, [M+H]+=240.0/242.0, using the following method:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>O>[CH2:1]([O:8][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCCCCCCCBr
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCCCCCCCCCOCc1ccccc1
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a mixture of 2.16 g of benzyl alcohol and 30 ml of dimethylformamide was added 1.2 g of oily sodium hydride (60%). After stirring the mixture for 30 minutes at 20° to 25° C., 10 g of 1,12-dibromododecane was added to the mixture in one portion followed by stirring for 2 hours at 25° to 30° C. After the reaction was over, 300 ml of water was added to the reaction mixture and the product was extracted with n-hexane. The extract was washed with water, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The oily residue was applied to silica gel column chromatography and eluted with a mixture of n-hexane and ether (9:1) to provide 3.8 g of 12-benzyloxy-1-bromododecane as an oily product.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:14])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[O:14])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a 3-necked round-bottomed flask was added AlCl3 (32 g, 0.24 moL) followed by anhydrous toluene (250 mL). The flask was equipped with a reflux condenser and nitrogen inlet and the suspension was stirred at RT under a nitrogen atmosphere. To the stirred suspension was added methyl 4-{[4-(methyloxy)phenyl]carbonyl}benzoate (23) (16.0 g, 0.059 moL) portionwise at RT under a nitrogen atmosphere. The reaction mixture was heated at 85° C. with stirring under a nitrogen atmosphere. After 2 h, the oil bath was removed and the reaction mixture was allowed to cool at RT. The reaction mixture was cooled in an ice-water bath and ice was added very slowly portionwise (Note: significant HCl evolved upon addition of ice to the reaction mixture.) followed by the slow addition of ice-water. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as a red-brown solid. The crude product was triturated with hot hexanes and the brown solid was filtered to give 14.0 g (93%) of compound 24. 1H NMR (400 MHz, DMSO-d6): δ 3.88 (s, 3H), 6.88 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.74 (d, J=8.2 Hz, 2H), 8.07 (d, J=8.2 Hz, 2H), 10.51 (s, 1H).
Reaction SMILES: [CH2:1]1[O:22][P:20]([OH:23])(=[O:21])[O:19][C@H:3]2[C@@H:4]([OH:18])[C@H:5]([N:7]3[C:16]([Br:17])=[N:15][C:9]4[C:10]([NH2:14])=[N:11][CH:12]=[N:13][C:8]3=4)[O:6][C@H:2]12.C1N=C(N)C2N=CN([C@@H]3O[C@@H]4COP(O)(O[C@H]4[C@H]3O)=O)C=2N=1.C(O)(=O)C.C([O-])(=O)C.[BrH:54]>>[CH:12]1[N:11]=[C:10]([NH2:14])[C:9]2[N:15]=[CH:16][N:7]([C@@H:5]3[O:6][C@@H:2]4[CH2:1][O:22][P:20]([OH:23])([O:19][C@H:3]4[C@H:4]3[OH:18])=[O:21])[C:8]=2[N:13]=1.[Br:54][Br:17]
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Reactant: Br
Agent: CC(=O)[O-]
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Solvent: CC(=O)O
Product: BrBr

Procedure:
A key reagent in the preparation of many of the compounds according to the invention is 8-Br-cAMP. Up until now, reports in the literature only refer to small scale preparations (e.g. <100 mg) of this material using dilute (0.1M) solutions of cAMP in an acetic acid/acetate medium. Attempts to use similar dilute conditions in larger scale work resulted in problems due to the large volumes of solvent required. We have now found that the procedure may be scaled up using concentrated solutions of cAMP with a concentrated buffer to scavenge the HBr that is produced during the reaction of cAMP with bromine. By using concentrated cAMP solutions, a two-fold benefit is also achieved—the proportion of the 8-Br-cAMP product that is precipitated out as if forms is optimised (thus making product collection easier) and the cAMP(H) starting material contributes to the buffer system. Thus for example 0.2M cAMP(H) and 0.4M sodium acetate creates a buffer system equivalent to 0.2M NaOAc/AcOH with a pH which remains stable during the bromination at about 4.7.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.Cl>O>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
An eggplant flask was charged with 4-fluoro-3-nitrobenzoic acid (2.51 g, 13.56 mmol), aniline (2.52 g, 27.12 mmol), and ethanol (9.5 mL), and this was heated to reflux with stirring for 16 hours. After cooling to room temperature, the mixture was poured into dilute hydrochloric acid (1 M, 50 mL), diluted with distilled water (100 mL), was left to stir as is at room temperature for 30 minutes. The precipitated crystals were filtered off, and washed successively with dilute hydrochloric acid (1 M, with approx. 3 mL 3 times), distilled water (approx. 5 mL 2 times), and with diethyl ether (approx. 3 mL). The crystals obtained were dried at reduced pressure with heating to yield the title compound (3.39 g, quant.) as a reddish-orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])([O-])=O.O.O.Cl[Sn]Cl.[BH4-].[Na+]>C(OCC)(=O)C.C(O)(C)(C)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10]
Reactant: C=CCOC(=O)COc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)COc1cccc(N)c1
Reaction time: 2 h
Yield: 59.8 %

Procedure:
Allyl 3-nitrophenoxyacetate (5 g, 0.021M) was dissolved in a mixture of ethyl acetate (45 ml) and t-butanol (5 ml), and SnCl2.2H2O (23.79 g, 0.105M) added. After stirring and heating at 60° for 1 hour, sodium borohydride (399 mg, 0.0105M) was added in portions, and heating continued for another 2 hours. Solvent was removed, the residue was taken up in water, and the pH adjusted to 7.6 with aqueous NaHCO3. Organics were extracted into ethyl acetate, and the combined organic layers washed with aqueous NaHCO3, water, brine, and dried (MgSO4). Evaporation gave the title compound (2.61 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(CN)O.OCCN1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:27]>>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[C:14](=[O:27])[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:20]=2[C:21](=[CH:24][CH:25]=[CH:26]3)[C:22]1=[O:23]
Reactant: NCCCO
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCO
Solvent: NCCO
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCO

Procedure:
Following the procedure of example 1(a) and (b) but substituting 3-aminopropanol for the ethanolamine in part (a) one obtains 2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, 4-methylbenzenesulfonate ester.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:22](=[O:23])[CH2:21][C@@H:19]2[CH2:18][S:17][C:16]([C:13]3[NH:14][C:15]4[C:11]([CH:12]=3)=[CH:10][C:9]([F:25])=[CH:8][C:7]=4[NH:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[N:20]2)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Product: CC(=O)N1CCN(C(=O)C[C@@H]2CSC(c3cc4cc(F)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Yield: 55 %

Procedure:
The compound (100 mg, 0.28 mmol) prepared in Example 37 and 1-acetylpiperazine instead of 1-methylpiperazine were reacted according to the same procedure as Example 84 to give the title compound (60 mg, Yield 55%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][CH2:13][C@@H:14]2[CH2:18][S:17][C:16]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=4[NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:15]2)[CH:8]=[N:9][C:10]=1[CH3:11])=[O:5])C.CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:28][C:24]1[CH:25]=[C:26]2[C:21](=[C:22]([NH:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:23]=1)[NH:20][C:19]([C:16]1[S:17][CH2:18][C@@H:14]([CH2:13][CH2:12][N:7]3[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[N:9]=[CH:8]3)[N:15]=1)=[CH:27]2
Reactant: CCOC(=O)c1c(C)ncn1CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncn(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
The compound (35 mg, 0.07 mmol) prepared in Example 109 was dissolved in tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml). Lithium hydroxide monohydrate (29 mg, 0.70 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, 1N hydrochloric acid solution was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (17 mg, Yield 52%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=1.[BH4-].[Na+].O.C(Cl)(Cl)Cl>C(O)C>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]([OH:12])[CH2:11][C:5]=2[CH:4]=1
Reactant: O=C1Cc2cc(C(F)(F)F)ccc2Sc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: OC1Cc2cc(C(F)(F)F)ccc2Sc2ccccc21
Temperature: 30 °C

Procedure:
12 g of 10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]-thiepin-10-one are dissolved in 110 ml of absolute ethanol and treated with 4 g of sodium borohydride. The mixture is held at reflux for 12 minutes, cooled to 30° C and treated with 350 ml of water and 100 ml of chloroform. After equilibration, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin-10-ol in the form of yellow crystals which melt at 122°-123° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:9]=[C:8]([CH3:21])[N:7]=1.[H][H]>O1CCOCC1.CO.[Ni]>[NH2:12][C:11]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]([CH3:21])=[CH:9][C:10]=1[O:15][CH2:16][C:17]([F:18])([F:19])[F:20]
Reactant: COCCOc1nc(C)cc(OCC(F)(F)F)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: COCCOc1nc(C)cc(OCC(F)(F)F)c1N

Procedure:
2-[(2-Methoxyethyl)oxy]-6-methyl-3-nitro-4-[(2,2,2-trifluoroethyl)oxy]pyridine (1.65 g, 5.32 mmol) was dissolved in a mixed solvent of dioxane (30 mL)-methanol (30 mL). Raney nickel (ethanol suspension, 3 mL) was added to the solution. In a hydrogen atmosphere, the mixture was stirred at room temperature for 26 hours. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 3-amino-2-[(2-methoxyethyl)oxy]-6-methyl-4-[(2,2,2-trifluoroethyl)oxy]pyridine as a pale yellow oil (1.49 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:16]/[C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[C:14]=3[F:21])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cccc(Cl)c1F
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 89 %

Procedure:
To the mixture of 6-chloro-2-oxindole (11 g, 65.6 mmol) (Crescent) and 3-chloro-2-fluorobenzaldehyde (12 g, 75.7 mmol) (Aldrich) in methanol (140 mL) was added piperidine (5.59 g, 65.6 mmol) (Aldrich) dropwise. The mixture was then heated at 50° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield 18 g, 89%).