Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:33])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O1CCCC1.CO.O>C(O)(=O)C>[CH2:3]([NH:10][C:11](=[O:33])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[N:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OCC)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
200 mg (5 mmol, 4 eq) of sodium hydroxide are added to a solution of 488 mg (1.14 mmol, 1 eq) of ethyl 3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}propanoate in 6 mL of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirred for 3 hours at room temperature. The reaction is stopped by adding 20 ml of water and 3 ml of acetic acid and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 to 50/50 heptane/ethyl acetate). The oil obtained is crystallized from pentane. 442 mg of 3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}propanoic acid are obtained. Yield=94%. m.p.=118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:32]([Mg]Cl)[CH2:33][CH3:34].C(OCC)(=O)C.C(OC(C)C)(C)C>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH2:32][CH2:33][CH3:34])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCC[Mg]Cl
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: CCCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 313, the title compound was synthesized using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde and a solution (2M) of propyl magnesium chloride in diethyl ether. Crystals (ethyl acetate-diisopropyl ether).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:29][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[S:8][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of [4-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.35 g), tetrahydrofuran (50 mL) and toluene (50 mL) was added a solution (5 mL) of thionyl chloride (1.5 mL) in toluene under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give colorless crystals (4.10 g, 89%) of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole. melting point: 98-99° C.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=1)=O)C>C(O)C>[CH3:14][CH:13]([C:11]1[N:12]=[C:8]([CH2:6][OH:5])[S:9][CH:10]=1)[CH3:15]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1csc(CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Sodium borohydride (40.4 g, 1.07 mol) was added in portions over 5-6 min to a cooled (5° C.) solution of 4-(1-methylethyl)thiazole-2-carboxylic acid ethyl ester (Example 12; 193 g, 0.97 mol) in ethanol (1.0 L). The solution was allowed then to stir at room temperature overnight. Examination of the reaction by tlc showed that a minor amount of starting ester remained. A second portion of sodium borohydride (4.0 g, 107 mmol) was added and after the mixture was stirred at ambient temperature for 40 min, the volatiles were removed under reduced pressure. Water (1.5 L) was added and the mixture was adjusted to pH 5-6 using acetic acid, then was extracted with chloroform (3×500 mL). The organic extracts were washed with brine (500 mL), dried (MgSO4), filtered and concentrated in vacuo to give 125 g of the crude alcohol as an oil. The oil was slurried in diethyl ether/hexane (1:19, 500 mL) and after the mixture was cooled, the resulting solids were collected by filtration, were washed with hexane and dried to give 4-(1-methylethyl)thiazole-2-methanol (102.6 g, 67.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([NH:24]C(=O)C(F)(F)F)[CH:3]=1.[Cl-].[Na+]>N1CCCCC1>[NH2:24][C:4]1[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=1[C:6]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(Cl)cc1NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCNCC1
Product: Nc1cc(Cl)ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.7 %

Procedure:
0.5 g (0.00113 mol) of 1-benzyl-piperidin-4-yl 4-chloro-2-trifluoroacetamido-benzoate was dissolved in 10 ml of 1N aqueous piperidine in an ultrasound bath for 1/2 hr. and subsequently stirred at room temperature for 48 hrs. The suspension was treated with semi-saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were dried over sodium sulfate and concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2). 0.256 g (65%) of 1-benzyl-piperidin-4-yl 2-amino-4-chloro-benzoate was obtained as a colorless oil. MS: me/e=345 (C19H22CIN2O2 +).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30](=[O:33])[CH2:31]Br.O>CN(C)C=O>[CH3:28][O:29][C:30](=[O:33])[CH2:31][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:3]2[C:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[S:6][C:5]=3[CH:13]=[CH:14][C:2]=2[Br:1])=[CH:16][CH:17]=1
Reactant: Oc1ccc(-c2c(Br)ccc3sc4ccccc4c23)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2c(Br)ccc3sc4ccccc4c23)cc1
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 4-(2-bromo-dibenzothiophen-1-yl)-phenol (0.480 g, 1.35 mmol) and potassium carbonate (0.385 g, 2.79 mmol, 2.06 eq) in anhydrous N,N-dimethylformamide (3 mL) was added methylbromoacetate (0.255 mL, 2.07 mmol, 2 eq) dropwise at room temperature under a dry nitrogen atmosphere. After stirring 24 hours the reaction mixture was poured into water (100 mL) and the organics were extracted into ether (100 mL) The ether was washed with water (100 mL) and brine (100 mL). Silica gel was added and the solvents removed. The adsorbate was flash chromatographed (55/45 petroleum ether/methylene chloride) and dried in vacuo at 58° C. to provide the title compound as a white solid (0.509 g, 88%); mp 122-122.5° C. NMR (DMSO-d6), δ 8.02 (d, J=8 Hz, 1H), 8.00 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.26-7.20 (m, 2H), 7.19 -7.16 (m, 2H), 7.13-7.09 (ddd, J=8,7,1, 1H), 6.53 (d, J=8 Hz 1H), 4.94 (s, 2H), 3.75 (s, 3H), MS [PBEI] M*+ m/z=426(100%), 428(98%), 1 bromine isotope pattern detected, Anal. Calc. for C21H15O3SBr: C, 59.03, H, 3.54, N, 0.00. Found: C, 58.91, H, 3,27, N, -0.02.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](Cl)=[O:25]>>[CH3:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: Cc1ccsc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 82.7 %

Procedure:
Beginning with 0.40 gm (1.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.34 gm (2.08 mMol) 3-methyl-2-thiophenecarbonyl chloride, 0.51 gm (83%) of the title compound were prepared as a light brown foam essentially by the procedure described in Example 4. A sample was crystallized from ethanol/water for analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[CH2:33]([N:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:46](O)=[O:47])[C:41]1=[O:49])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([N:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:46]([NH:1][C:2]2[CH:31]=[CH:30][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[CH:17]=[CH:18][C:19]([C:22]([N:24]6[CH2:25][CH2:26][O:27][CH2:28][CH2:29]6)=[O:23])=[CH:20][CH:21]=5)[S:15][C:8]=34)=[C:4]([F:32])[CH:3]=2)=[O:47])[C:41]1=[O:49])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Reactant: O=C(O)c1nccn(Cc2ccccc2)c1=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1)c1nccn(Cc2ccccc2)c1=O
Yield: 45 %

Procedure:
Prepared from (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A) and 4-benzyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2) to afford 12 mg (45%) of the desired product. LRMS (APCI pos) m/e 662.2 (M+1). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.03 (dd, 1H), 7.96 (d, if H), 7.92 (d, 2H), 7.85 (s, if H), 7.77 (d, 1H), 7.56 (m, 3H), 7.36-7.46 (m, 7H), 6.66 (d, 1H), 5.33 (s, 2H), 3.68-3.81 (m, 8H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −128.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a suspension of 15.0 g of methyl 4-benzyloxybenzoate in 225 ml of methanol were added 18.6 ml of a 5N solution of sodium hydroxide. The mixture was heated at reflux for 18 hours. The solution was cooled to room temperature and acidified to pH 3 by addition of 6N hydrochloric acid. The resulting white precipitate was filtered to give 13.6 g of the title compound: 300-MHz 1H NMR (DMSO-d6) δ5.18 (s, 2 H), 7.04 (d, J=9 Hz, 2 H), 7.26-7.49 (m, 5 H), 7.86 (d, J=9 Hz, 2 H), 12.3 (b s, 1 H).
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Cl)(OC(C)(C)C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[CH2:37]1[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[N:43][C:44]=2[CH:35]([N:34]([CH2:17][C:9]2[NH:8][C:12]3[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:20]3[N:19]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:45])=[CH:28][CH:29]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: O=C(Nc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccn1)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 47.6 %

Procedure:
N-BOC-chloromethylbenzimidazole (115 mg, 0.43 mmol), N-Pyridin-2-yl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)methyl]-benzamide (AMD9362) (155 mg, 0.43 mmol), and K2CO3 (179 mg, 1.29 mmol) were heated to reflux in CH3CN (3 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, followed by radial chromatography on silica gel (2 mm plate, 3:3:94 CH3OH—NH3 H2O—CH2Cl2), afforded AMD9370 (100 mg, 47%) as white foam. 1H NMR (CDCl3) δ 1.68-1.75 (m, 1H), 1.97-2.08 (m, 2H), 2.26-2.32 (m, 1H), 2.71-2.84 (m, 1H), 2.86-2.91 (m, 1H), 3.84 (s, 2H), 3.95 (d, 1H, J=16.5 Hz), 4.08-4.14 (m, 1H), 4.22 (d, 1H, J=16.0 Hz), 7.03-7.07 (m, 1H), 7.16-7.22 (m, 3H), 7.45 (d, 1H, J=6.9 Hz), 7.52-7.61 (m, 3H), 7.65 (d, 1H, J=7.5 Hz), 7.73 (ddd, 1H, J=1.8, 7.2, 8.7 Hz), 7.80 (d, 2H, J=8.1 Hz), 8.27-8.29 (m, 1H), 8.33 (d 1H, J=8.4 Hz), 8.44 (br, s, 1H), 8.72-8.80 (m, 1H); 13C NMR (CDCl3) δ 21.72, 23.30, 29.56, 49.29, 54.16, 60.83, 111.39, 114.52, 120.17, 122.29, 122.81, 127.72, 129.28, 133.58, 135.17, 137.76, 138.77, 144.61, 147.38, 148.21, 152.00, 156.13, 157.54, 165.99; ES-MS m/z 489.2 (M+H); Anal. Calcd. for (C30H28N6O).0.6(H2O).0.7(CHCl3): C, 63.25; H, 5.17; N, 14.42. Found: C, 63.56; H, 5.25; N, 14.31.
Reaction SMILES: [OH:1][C:2]1[C:15](CCC)=[C:14](O)[CH:13]=[CH:12][C:3]=1[C:4](C1C=CC=CC=1)=O.[NH2:20]O.Cl.CC([O-])=O.[Na+]>CCOC(C)=O>[O:1]1[C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[CH:4]=[N:20]1
Reactant: NO
Reactant: CCCc1c(O)ccc(C(=O)c2ccccc2)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: c1ccc2oncc2c1

Procedure:
The 2,4-dihydroxy-3-propylbenzophenone (2.5 g, 1.0 Eq, 9.8 mmol) was converted to the oxime with NH2OH--HCl (2.7 g, 4.0 Eq, 39 mmol) and NaOAc (3.21 g, 4.0 Eq, 39 mmol) as in Example 7 Step A. The oxime was purified by elution from a silica gel column (180 g E. Merck 40-63μ) with 97:3 Toluene: EtOAc. The product oxime (1.82 g) was further treated as in Example 7 Step A with acetic anhydride (15 ml) and subsequent reflux in pyridine (15 ml). The cooled reaction mixture was poured into 2 N Hcl and EtOAc. The aqueous phase was extracted with EtOAc and washed with sat'd aq NaHCO3, followed by sat'd aq NaCl. The EtOAc extracts were dried over Na2SO4 and reduced i. vac. The residue was taken up in refluxing toluene (50 ml). The product benzisoxazole is obtained as colorless crystals upon cooling to RT.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27]>>[OH:27][C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][N:24]([CH3:23])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNC[C@H](O)c1ccccc1
Product: CN(C[C@H](O)c1ccccc1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-2-(methylamino)-1-phenylethanol (1.2 equiv) to give 156 (19.1 mg, M+1 447.1)
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][CH:14]=[CH:15][C:16]=2[CH2:17]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>>[C:5]1([C:11]2[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][CH:14]=[CH:15][C:16]=2[CH2:17][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCc1ccnc(-c2ccccc2)c1-c1ccccc1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: c1ccc(-c2nccc(CN3CCCCC3)c2-c2ccccc2)cc1
Yield: 71 %

Procedure:
Thionyl chloride (1 mL) (Wako Pure Chemical Industries, Ltd.) was added to Compound 9 described above (0.30 g, 1.15 mmol), and the mixture was refluxed for 30 minutes. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in acetonitrile (20 mL), and piperidine (0.75 g, 8.80 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto, followed by reflux for 3 hours. The mixture was returned to room temperature, and then a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added thereto, followed by extraction with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.27 g, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[Cl:14])[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Agent: Cl
Product: Clc1ccc2nc(CN3CCN(c4ccccc4Cl)CC3)cn2c1

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4. Step 1; 0.289 g) and 1-(2-chlorophenyl)piperazine monohydrochloride (Aldrich; 0.381 g) give, after crystallization from ethyl acetate/hexane, 0.2423 g of the title compound; mp 123-123.5° C.; MS m/z 360; IR (mineral oil) 1325, 1475, 1039, 2818, 2810 cm-1 ; 1H NMR (CDCl3) δ2.77, 3.12, 3.79, 6.96, 7.04, 7.12, 7.21, 7.34. 7.52. 8.14.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>ClCCl>[C:23]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][CH2:6]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1CCN(C(=O)c2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 3.5 h

Procedure:
To a suspension of N-(piperidin-4-yl)-4-fluorobenzamide (0.5 g) in dichloromethane (5 ml) were added pyridine (218 μl), dichloromethane (5 ml) and benzoyl chloride (290 μl) at ambient temperature. After stirring for 3.5 hours, water (5 ml) was poured into the mixture. An organic layer was separated, and washed with water and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel, toluene:ethyl acetate=1:1 to ethyl acetate). After rinse with diisopropyl ether, N-(1-benzoylpiperidin-4-yl)-4-fluorobenzamide (515 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:14]1[CH2:22][CH2:23][O:24][CH:13]1[C:12]1[CH:15]=[CH:16][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=2)=[C:10]([O:17][CH3:18])[CH:11]=1
Reactant: OCCO
Reactant: COc1cc(C=O)ccc1Oc1ccc(N)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C2OCCO2)ccc1Oc1ccc(N)c([N+](=O)[O-])c1

Procedure:
4-[(4-amino-3-nitrophenyl)oxy]-3-(methyloxy)benzaldehyde (2.42 g, 8.4 mmol), ethyleneglycol (4 ml) and p-toluenesulfonic acid (50 mg) in 50 mL of toluene was heated at 125 degrees Centigrade with a Dean-Stark trap for approximately 18 hours. The reaction mixture was diluted with ethyl acetate and washed twice with saturated NaHCO3. The aqueous layers were extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated to give 4-{[4-(1,3-dioxolan-2-yl)-2-(methyloxy) phenyl]oxy}-2-nitroaniline. (M+1) 332.9, 2.13 min (LC/MS method B)
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C.O>[N+:17]([C:8]1[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2ccc3cccc4ccc1c2c34

Procedure:
A solution was prepared by dissolving 101 g of pyrene in 800 ml of glacial acetic acid. While heating this solution at 50° C. in water bath with stirring, a mixed solution of 42 ml of nitric acid (D=1.4) and 50 ml of glacial acetic acid was slowly added thereto dropwise. At the end of 30 minutes, the reacted mixture was filtered with suction. The precipitate was washed with a small quantity of glacial acetic acid and then thoroughly washed with water to obtain 115 g of yellow crystals (melting point: 150° C.). By recrystallizing these crystals in glacial acetic acid, crystals having a melting point in the range of 153°~154° C. were obtained. The result of elemental analysis of this product was as shown in the following table:
Reaction SMILES: C([O:8][C:9]1[CH:43]=[CH:42][C:12]2[C:13]3[CH:14]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:29][CH:28]=4)[N:15]([CH3:26])[C:16]4[CH:17]=[C:18]([F:25])[CH:19]=[CH:20][C:21]=4[C:22]=3[CH:23]=[CH:24][C:11]=2[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].C(O)C>[F:25][C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH:23]=[CH:24][C:11]4[CH:10]=[C:9]([OH:8])[CH:43]=[CH:42][C:12]=4[C:13]=3[CH:14]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:31][CH:32]=3)[N:15]([CH3:26])[C:16]=2[CH:17]=1
Reactant: CN1c2cc(F)ccc2-c2ccc3cc(OCc4ccccc4)ccc3c2C1c1ccc(OCCN2CCCCC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Product: CN1c2cc(F)ccc2-c2ccc3cc(O)ccc3c2C1c1ccc(OCCN2CCCCC2)cc1
Yield: 79.7 %

Procedure:
To a round bottom flask add 2-benzyloxy-8-fluoro-6-methyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6-dihydro-benzo[i]phenanthridine (0.030 g, 0.052 mmol), ammonium formate (0.026 g, 0.42 mmol), methanol (5 mL) and a slurry of 10% Pd/C (0.005 g, ˜15% by weight) and ethanol (2 mL). Heat the mixture, with stirring, at reflux for 30 minutes. Cool the reaction to ambient temperature and filter it through a pad of Celite, then rinse the Celite with hot methanol. Evaporate the filtrate in vacuo and purify the resulting residue by radial chromatography over silica (5-10% MeOH gradient in CH2Cl2) to provide the product 20 mg (80%); mass spectrum (ion spray) m/z=483 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>O1CCCC1.[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: Cn1ccnc1N1CCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1ccnc1N1CCc2cc(N)ccc21
Reaction time: 1 h

Procedure:
170 mg 1-(1-methyl-1H-imidazol-2-yl)-5-nitro-2,3-dihydro-1H-indole are dissolved in 20 ml of tetrahydrofuran. To this are added 20 mg palladium on charcoal (10%) and the mixture is hydrogenated for 1 hour at ambient temperature. Then the catalyst is filtered off and the solvent is eliminated in vacuo. The crude product is extracted from diethyl ether.