Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[N:6]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][N:39]([CH:50]1[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]1)[C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][C:43]=2[N:44]=1.CC(C)=O>CN(C=O)C>[CH3:38][N:39]([CH:50]1[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]1)[C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46]([NH:49][C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)=[CH:15][CH:14]=3)=[CH:45][C:43]=2[N:44]=1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)cs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(=O)Nc3ccc4oc(N(C)C5CCN(C)CC5)nc4c3)cc2)cs1
Yield: 106.5 %

Procedure:
Combine 4-(2-methyl-1,3-thiazol-4-yl)benzoic acid (55 mg, 0.251 mmol), TBTU (74 mg, 0.232 mmol), and N2-Methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (46 mg, 0.177 mmol) in DMF (1.0 mL) and shake at room temperature. Add acetone (2.0 mL) a put the mixture on an SCX cartridge (previously conditioned with MeoH). Wash with acetone (3×3.0 mL) non basic impurities and then with MeOH (3×3.0 mL). Eluting with a 2N solution of NH3 in MeOH (4.0 ml) and concentrate to afford the title compound (87 mg, 100%). LC/MS, RT=4.45 min., mass spectrum (m/z) found (M+H)+: 462.2. The material is dissolved in MeOH and treated with 2M HCl in ether (2.0 mL). Organic solvent is removed in vacuo and the resulting precipitate is collected to give 96 mg of the hydrochloride salt.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Br:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(F)cc1Br
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)cc4Br)c3c2s1
Yield: 44 %

Procedure:
Prepared from VII and 2-bromo-4-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 95:5). Yield: 44%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3068, 2853, 2228, 1736, 1644, 1611, 1582, 1497, 1474, 1459, 1380, 1353, 1309, 1252, 1188, 1171, 1127, 1050, 1031, 980, 881, 860, 826; 19F NMR (282 MHz, DMSO-d6) δ −119.33; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, 1H, J=9.0 Hz), 8.18 (s, 1H), 7.81 (d, 1H, J=9.0 Hz), 7.63 (d, 1H, J=7.8 Hz) 7.24-7.17 (m, 2H); HRMS calcd for C16H8N5SBrF (M+H+): 399.9668, found 399.9675.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)=O)=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:18]/[C:19](=[N:37]\[OH:38])/[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([C@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)c1ccc([C@H](C/C(=N\O)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 1, step 2, from 2-{4-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-malonic acid diethyl ester and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a mixture of E and Z isomers (2.7:1) as a white oil, MS (ESI+): m/z=489.3 ([M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])=[CH:6][N:5]=[C:4]([NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:3]=1.C(OCC)(=O)C.O.[F:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>O1CCOCC1.C(N(CC)CC)C>[O:23]=[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[CH2:12][CH2:11][CH2:10][C:9]#[C:8][C:7]1[C:2]([NH:45][C:44]2[CH:46]=[CH:47][C:41]([F:40])=[CH:42][CH:43]=2)=[N:3][C:4]([NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)=[N:5][CH:6]=1
Reactant: Nc1ccc(F)cc1
Reactant: N#Cc1ccc(Nc2ncc(C#CCCCN3C(=O)c4ccccc4C3=O)c(Cl)n2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(Nc2ncc(C#CCCCN3C(=O)c4ccccc4C3=O)c(Nc3ccc(F)cc3)n2)cc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((4-chloro-5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)pyrimidin-2-yl)amino)benzonitrile (J13, 41 mg) in 1,4-dioxane (1.5 mL), 4-fluoroaniline (79 μL) and triethylamine (115 μL) were added at room temperature, and the mixture was stirred at 95° C. for 2 hours in a sealed tube. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with 1.0 mol/L aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid matter was washed with a mixed solvent of chloroform and methanol, and then dried under reduced pressure to obtain 4-((5-(5-(1,3-dioxoisoindolin-2-yl)-1-pentyn-1-yl)-4-((4-fluorophenyl)amino)pyrimidin-2-yl)amino)benzonitrile (J14, 32 mg) as pale green solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(CNC(=O)OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc(CNC(=O)OCc2ccccc2)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture comprising 20 g of N-benzyloxycarbonyl-3-hydroxy-4-methoxybenzylamine, 17.43 g of ethyl bromoacetate, 14.43 g of potassium carbonate and 200 ml of 2-butanone, was refluxed under heating with stirring overnight. The mixture was cooled to room temperature. Then, inorganic substances were filtered off, and the filtrate was distilled under reduced pressure. The obtained residue was extracted with chloroform, and the organic layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was crystallized from diethyl ether/n-hexane to obtain 17.83 g of the above-identified compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N+:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][NH:21][CH2:22]2)([O-:16])=[O:15]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[CH:26][C:17]=4[N+:14]([O-:16])=[O:15])[CH2:22]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cccc2c1CCNC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2c(cccc2[N+](=O)[O-])C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Nitro-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[NH:18][N:19]=[C:20]4[C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(OCC)(=O)C.CCCCCC>[C:38]([N:19]1[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=2[C:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[N:18]1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: Fc1ccc(N2CCN(CCCc3[nH]nc4c3CCCC4)CC2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)n1nc(CCCN2CCN(c3ccc(F)cc3)CC2)c2c1CCCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole (3.1 g), dimethylformamide (30 ml) and triethylamine (2.5 ml) was dropwise added acetyl chloride (0.72 ml) under ice-cooling. The mixture was stirred as it was for 30 minutes. The reaction mixture was poured into ice water (200 ml). The mixture was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to give 3.4 g of an oily substance. The oil was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:2) to give 0.60 g of 1-acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1H-indazole (component eluted later (compound A)), and 0.30 g of 2-acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole (component eluted first (compound B)). 1-Acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1H-indazole (compound A: m.p. 60-61° C.); 2-Acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole (compound B: m.p. 104-106° C.).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=O)=O.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A solution of 4-nitrobenzyl methanesulfonate (2.2 g, 9.51 mmol) in dimethylformamide (10 mL) was added potassium phthalimide (1.9 g, 10.5 mmol) and stirred at room temperature for overnight. TLC showed complete consumption of starting material. The mixture was extracted with ethyl acetate and washed with water and brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by crystallization to give 2-(4-nitrobenzyl)isoindoline-1,3-dione (1.6 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[S:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:22]([NH2:24])=[O:23].[Cl-].[NH4+].C(O)C.O>[Fe].CO.C(OCC)(=O)C.CN(C)C=O>[NH2:19][C:16]1[S:15][C:14]([S:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:22]([NH2:24])=[O:23])[CH:5]=3)[N:10]=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Sc3ccc([N+](=O)[O-])s3)c2cc1C(N)=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2nccc(Sc3ccc(N)s3)c2cc1C(N)=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
After suspending 7-methoxy-4-(5-nitrothiophen-2-ylsulfanyl)quinoline-6-carboxamide (320 mg, 0.885 mmol), iron (247 mg, 4.43 mmol) and ammonium chloride (481 mg, 8.85 mmol) in an ethanol (8 ml)-water (2 ml)-dimethylformamide (1 ml) mixed solvent, the suspension was heated and stirred at 80° C. for 15 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in a tetrahydrofuran-methanol mixed solvent. After adding ethyl acetate to the organic layer, it was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=20:1), and the fraction containing the target substance was concentrated to obtain the title compound (164 mg, 0.495 mmol, 56%) as yellowish-brown crystals.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:20])[NH:6]1)=[N+]=[N-].[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[CH:22]=O>C(O)(=O)C.C(Cl)Cl.[Zn]>[CH2:26]([O:25][C:21](=[O:24])[CH:22]=[N:1][CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:20])[NH:6]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1
Reactant: O=CC(=O)OCc1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(C=NC[C@@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
cis-2-Azidomethyl-3-benzyloxycarbonylamino-4-oxoazetidine is treated with zinc dust in 50% aqueous acetic acid as described in Preparation 7. Reaction of the crude reduction product with benzyl glyoxalate in methylene dichloride as described in the procedure of Example 1 gives N-(cis-3-benzyloxycarbonylamino-4-oxo-2-azetidinyl-methyl)iminoacetic acid benzyl ester which, when treated with acetyl chloride according to the procedure of Example 1, gives 3-acetyl-6β-benzyloxycarbonylamino-7-oxo-1,3-diazabicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.[NH2:13][C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][C:15]=1[C:23](=[O:25])[CH3:24].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:23]([C:15]1[C:14]([NH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([C:2]([F:1])([F:12])[F:11])[N:4]=2)=[O:10])=[C:19]([CH3:20])[C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:25])[CH3:24]
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1C
Yield: 74 %

Procedure:
Compound 64b was synthesized from 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid and 1-(2-amino-4-methoxy-3-methylphenyl)-ethanone as a beige solid in 74% yield, following the procedure as described for compound 42a.
Reaction SMILES: B.CSC.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=O)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl.[OH-].[Na+]>C1COCC1.O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:27][CH2:28]3)[CH2:19][CH2:20]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: O=S(=O)(c1ccc(Br)cc1)N1CCN(CC2CCN(c3ccncc3)CC2)CC1
Reaction time: 18 h
Yield: 53.7 %

Procedure:
Borane-dimethylsulphide (0.5 ml; 10M) was added dropwise to a stirred suspension of 1-(4-bromophenylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine (493 mg) in THF (10 ml) at 0-5°. The mixture was stirred for 18 hours at 25°. 6M Hydrochloric acid (4 ml) was added dropwise and the mixture stirred for 1 hour, then for 0.25 hours at reflux and then for 1 hour at 20°. The mixture was basified to pH 12 with 2M sodium hydroxide. Water (5 ml) was added and the aqueous extracted with dichloromethane (2×25 ml). Combined organic phases were dried and evaporated to give a gum, Trituration with diethyl ether (2×40 ml) gave, as a colourless solid, 1-(4-bromophenylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylmethyl]piperazine (257 mg): m.p. 179-180° C:
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][CH:16]=[C:15]4[I:21])[CH:9]=[N:8][CH:7]=2)[CH2:5][CH2:4]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH:3]1([C:6]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:16]=[C:15]4[I:21])[CH:9]=[N:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Ic1c[nH]c2ccc(-c3cncc(C4CC4)n3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cncc(C5CC5)n4)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.4 %

Procedure:
NaH (60% in mineral oil) (34 mg, 0.85 mmol) was added to a solution of 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1H-indole (280 mg, 0.78 mmol) in THF (4 mL) at 0° C. The mixture was stirred for 10 min at 0° C. and p-toluenesulfonyl chloride (163 mg, 0.85 mmol) was added and the mixture was warmed to RT. After 1 h, water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1-tosyl-1H-indole (394 mg, 0.76 mmol, 99% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 516.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:40])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:41]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:40][C:3]1[C:2]2[N:1]=[CH:41][N:12]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:16]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CCOC([O-])[O-]
Reactant: Nc1c(Cl)nc2ccccc2c1NCCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc2ccccc2c2c1ncn2CCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 19.9 g of 3-amino-2-chloro-4-[2-(N-triphenylmethyl-4-piperidyl)-ethylamino]quinoline, 24.1 ml of ethyl orthoformate and 0.68 g of p-toluenesulfonic acid monohydrate in 200 ml of toluene was refluxed for 6 hours. After cooling, the precipitated crystals were collected by filtration, and washed with diisopropyl ether to give 16.4 g of colorless crystals. Recrystallization from a mixture of methanol and tetrahydrofuran gave colorless crystals having the melting point of from 229 to 234.5° C. (decomposition).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[CH3:28][NH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8](=[O:27])[N:29]([C@H:30]3[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]3)[CH3:28])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: CN[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N(C)[C@H]3CC[C@H](O)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with trans-4-methylamino-cyclohexanol and pyridine in chloroform. [α]D20=+20.5° (c=1.02, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1O)([O-:3])=O.[OH-].[Na+].C1C2C(=[O:44])C3C(=CC=CC=3)C=2C=CC=1.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.C(O)CCC>[OH:44][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:24])[CH3:25])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:19])[CH3:20])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:3])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(N=Nc2ccccc2)cc1
Solvent: O
Solvent: CCCCO
Product: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
2-nitro-2'-hydroxy-3',5'-di-t-amylazobenzene 25.5 g was added to a mixture of n-butanol 80 g, water 14 g and 97% sodium hydroxide 8.2 g, and the resultant mixture was stirred while raising temperature to 65° C. Thereafter, the mixture was cooled to 50° C., and 9-fluorenone 2.0 g was added to the mixture. The reaction mixture was then heated to 90° C. in one hour, and the mixture was stirred at 90°~96° C. for four hours to effect reaction, thus almost all of the azobenzene having disappeared to produce 2-(2-hydroxy-3,5-di-t-amylphenyl)benzotriazole-N-oxide. Thus, the reaction of Process (b) was finished.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=O)[CH:10]=1.[Cl-].[N:17]1([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([CH2:22][CH2:23][CH2:24][CH2:25][N:26]2[C:11](=[O:13])[C:9]3[CH:10]=[CH:1][CH:2]=[C:3]4[C:8]=3[C:7](=[CH:6][CH:5]=[CH:4]4)[C:14]2=[O:15])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: NCCCCn1ccnc1
Agent: [Cl-]
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCn1ccnc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3.0 g of 1,8-naphthalic anhydride, 50 ml of methyline chloride and 2.1 g of 1H-imidazole-1- butanamine was stirred at room temperature for 20 hours. The insoluble product was isolated by filtration, washed with methlene chloride and then ether and dried in vacuo. The solid was placed in a round-bottom flask and immersed in an oil bath at 150° C., and the temperature was increased over a 45 minute period to 165° C. The reaction mixture was allowed to cool and the residue was triturated with ethyl acetate and recovered by filtration. After recrystallization from ethanol, the desired product melted at 153°-155° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.CC(C)([O-])C.[Li+].[Cl-].[NH4+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:32]5[O:31][CH:35]=[CH:34][N:33]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: c1cocn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncco5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 106.8 %

Procedure:
A solution of the compound (250 mg, 0.49 mmol) obtained in Example 16-4), oxazole (68 mg, 0.98 mmol), tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.02 mmol), and lithium tert-butoxide (81 mg, 0.98 mmol) in dioxane (3 mL) was stirred for 2 h with heating to reflux. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (260 mg, quant.) in a yellow oily form.