Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C[C:11]1[CH:12]=[CH:13][C:14](S(O)(=O)=O)=[CH:15][CH:16]=1.O.C(CC(=O)C)C(C)=O.N1C=CC=C1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:15]([CH3:14])=[CH:16][CH:11]=[C:12]1[CH3:13]
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Solvent: c1cc[nH]c1
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(I)cc1F
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask was charged with 2-fluoro-4-iodoaniline (53.3 g, 220 mmol), toluene (250 mL), TsOH·H2O (0.43 g, 2.3 mmol, 1 mol %), and acetonylacetone (30.8 g, 270 mmol, 1.2 eq). The solution was warmed to reflux under Dean-Stark conditions for 1 h, at which point GC/MS and TLC analysis indicate complete conversion to the pyrrole. The solution is cooled to room temperature, washed with aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to provide a dark brown oil which crystallized upon standing (crude yield=72.8 g, 103% of theory). This material was homogeneous by HPLC and 1H nmr, and was suitable for use in the next reaction. An analytical sample was prepared by dissolving in 210 mL of hot hexanes, cooling, then concentrating to 50% of the original volume. Cooling in an ice bath with rapid stirring provided 35.5 g (49% recovery) of a brown, granular solid (m.p. 68-70° C.). 1H NMR (CDCl3): d 7.43 (t, J=27 Hz, 2H), 7.13 (t, J=20 Hz, 1H), 5.94 (s, 2H), 2.02 (s, 6H); 13C NMR (CDCl3) d 158.3 (d, J=254 Hz), 131.6, 128.9, 127.8 (d, J=3 Hz), 122.0, 120.3 (d, J=23 Hz), 106.4, 12.4; MS (El): m/z 268 (100).
Reaction SMILES: C[O:2][Si:3][O:4]C.[CH:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:12]3[N:44]=[C:43]4[N:45]=[C:36]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=54)[N:35]=[C:33]4[NH:34][C:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=54)=[N:25][C:23]4=[N:24][C:16]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=54)=[N:15][C:14]=2[NH:13]3)[CH:11]=1.O>CN1CCCC1=O>[OH:2][Si:3][OH:4].[CH:7]1[CH:6]=[CH:11][C:10]2[C:9](=[C:14]3[N:15]=[C:16]4[N:24]=[C:23]([C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=54)[N:25]=[C:26]4[NH:34][C:33]([C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=54)=[N:35][C:36]4=[N:45][C:43]([C:42]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=54)=[N:44][C:12]=2[NH:13]3)[CH:8]=1
Reactant: CO[Si]OC
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: O[Si]O
Temperature: 25 °C

Procedure:
10 g of dimethoxysilicon phthalocyanine synthesized in Synthesis Example 2 was added to 5 g of water and 95 g of N-methylpyrrolidone (95% NMP aqueous solution) and reacted at 115° C. for 3 hours. The reaction product was thermally filtrated and washed with NMP and acetone in the order named. After the product was stirred in 100 ml of acetone at room temperature, crystals were separated by filtration and dried to obtain 8.0 g of dihydroxysilicon phthalocyanine. Structural analysis was carried out by mass spectrum (negative measurement), IR spectrum (KBr method) and elemental analysis. FIG. 34 shows the mass spectrum of dihydroxysilicon phthalocyanine and FIG. 35 shows the IR spectrum thereof. In the mass spectrum, a peak of dihydroxysilicon phthalocyanine was observed at an m/z of 574. A peak at an m/z of 557 is a fragment peak at which one hydroxyl group is removed. In the IR spectrum, absorption special to dihydroxysilicon phthalocyanine was observed at 1,519, 1,066 and 839 cm-1. The results of elemental analysis are shown below and almost agree with calculation values. It was thereby confirmed that the product was dihydroxysilicon phthalocyanine.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH2:46][CH3:47])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:3][C:4](=[O:7])[O:5][N:41]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH2:46][CH3:47])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCc1nc(CC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-[(1-benzyl-4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.58 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.53 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.80 g, 65%) as a solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1([S:21](Cl)=[O:22])C=CN=C1>ClCCl>[CH3:12][C@H:11]1[C:13](=[O:15])[O:14][S:21](=[O:22])[N:10]1[C@@H:4]([CH2:3][CH2:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: O=S(Cl)n1ccnc1
Solvent: ClCCl
Product: CCC[C@@H](C(=O)OCC)N1[C@@H](C)C(=O)OS1=O
Reaction time: 1 h

Procedure:
Introduce into a reactor 200 g of N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine and 1.5 liters of dichloromethane and then, at 0° C., add 325 g of 1H-imidazole-1-sulphinyl chloride. Subsequently, bring the reaction mixture to ambient temperature and then, after stirring for 1 hour, filter off the precipitate formed. The filtrate obtained is evaporated to dryness to yield the expected product in the form of an oil.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8][NH:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH2:17][C:18]2[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=2)=[C:12]([Cl:28])[CH:11]=1)C.C(CC(NC(OCC)=O)=O)#N>>[Cl:28][C:12]1[CH:11]=[C:10]([N:9]2[C:4](=[O:3])[NH:5][C:6](=[O:31])[C:7]([C:29]#[N:30])=[N:8]2)[CH:15]=[C:14]([Cl:16])[C:13]=1[CH2:17][C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:27])[NH:20][N:19]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Cc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: CCOC(=O)NC(=O)CC#N
Product: CC(C)c1cc(Cc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Yield: 39 %

Procedure:
This compound was prepared by a similar method to that described in Example 8, Step 2 except that (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yl-methyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (47) was used in place of 2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (30) to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (48) as an off-white solid (1.21 g, 39%); EI(+)-HRMS m/z calcd for C18H14Cl2N6O3 (M+H)1+ 433.0577, found 433.0577. Molecular Weight=433.2567; Exact Mass=432.0504
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[OH-].[NH4+:28]>O1CCOCC1>[NH2:28][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([CH:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1cc(F)cc(F)c1)c1ncc(Cl)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(Cc1cc(F)cc(F)c1)c1ncc(N)nc1Cl
Temperature: 90 °C

Procedure:
In a high pressure reaction vessel, a suspension of 59B (300 mg, 0.742 mmol) in dioxane (2 mL) was treated with ammonium hydroxide (28%) (3 mL) and heated at 90° C. overnight. Solvents were removed and the crude was purified by flash chromatography to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ 8.17 (d, 1H), 7.33-6.97 (m, 2H), 6.84-6.31 (m, 4H), 5.25 (m, 1H), 4.65 (s, 1H), 3.42 (d, 2H), 3.27-2.96 (m, 6H), 2.47 (m, 2H), 1.38 (m, 1H), 1.05 (m, 1H). MS (m/z) 385 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.1 g, 9.8 mmol) was dissolved in 100 mL dry diethyl ether under an argon atmosphere, added dry pyridine (3.3 mL, 32.5 mmol), cooled to 0° C. then added oxalyl chloride (1.4 mL, 16.3 mmol) dropwise. A precipitate forms immediately upon addition of oxalyl chloride and therefore reaction requires vigorous stirring. Stirred at 0° C. for one hour than at ambient temperature for 2 hours. Dry diethyl ether (100 mL) was added and the solids were filtered off, washing with more diethyl ether. The filtrates were concentrated, then redissolved in dry DCM under argon, cooled to 0° C., added 1 mL dry pyridine then added 4-amino-benzonitrile (0.96 g, 8.1 mmol) in one portion. Stirred at ambient temperature for 2 hours, concentrated, redissolved in ethyl acetate (250 mL), washed with 10% citric acid (3×100 mL), water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white foam. (2.4 g, 93%) APCI (AP−): 314.1 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[CH:12]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]2[C:21]([O:23]C(=O)[C:14]=2[CH:13]=1)=[O:22].C([O-])(=O)C.[Na+]>CN(C)C=O.O.C(OC(=O)C)(=O)C.I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:14]2[CH:13]=[CH:12][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[C:21]([OH:23])=[O:22])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: I
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(CCc2ccc(Br)cc2)c(C(=O)O)c1

Procedure:
A mixture of 103.2 g. of p-bromophenylacetic acid, 77.4 g. of benzene-1,2,4-tricarboxylic anhydride and 1.5 g. of sodium acetate was heated to 275° for 2 hours. The residue was dissolved in 1600 ml of hot dimethylformamide and the solution diluted with 400 ml of water, then cooled. The solution was then filtered to afford a mixture of 3-(p-bromobenzylidene)phthalide-5- and -6-carboxylic acids. 80 g. of this mixture was refluxed for 72 hours in 160 ml of acetic anhydride and 240 ml of 57% aqueous hydriodic acid containing 35.2 g. of red phosphorus. The mixture was cooled in ice and diluted with 1000 water. The solution was filtered and the residue dissolved in 800 ml dimethylformamide and filtered. The filtrate was evaporated to yield a residue which upon recrystallization from benzene: ethanol (3:1) yielded 4-(p-bromophenethyl)benzene-1,3-dicarboxylic acid. The mother liquors were evaporated and the residue recrystallized from ethyl acetate to afford 2-(p-bromophenethyl)benzene-1,4-dicarboxylic acid. 8.5 G. of 2-(p-bromophenethyl)-benzene-1,4-dicarboxylic acid was stirred at 170° for 6 hours in a mixture of 40 ml of polyphosphonic acid and 30 ml of tetrahydrothiophene-1,1-dioxide. The mixture was then poured into water and the product filtered off and recrystallized from aqueous dimethylformamide to yield 2-carboxy-7-bromo-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene mp 252°-254°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10](Cl)[N:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:14][C:12]1[CH:13]=[C:8]([Cl:7])[N:9]=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:11]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cc(Cl)nc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
Morpholine (5.0 g) was added to a suspension of 2,4,6-trichloropyridine (10.0 g) and sodium carbonate (5.9 g) in acetonitrile (100 mL). The reaction mixture was then stirred at 70° C. for 16 hours, cooled to ambient temperature, filtered through celite and concentrated in vacuo. The crude product was subjected to flash chromatography (SiO2, heptane/ethylacetate 4:1) to furnish 3.90 g (30% yield) of the title compound as an off-white solid. LC-MS (m/z) 323.8 (M+); tR=3.10, (UV, ELSD) 98.5%, 98.9%. 1H NMR (500 MHz, CDCl3): 3.50 (m, 4H), 3.80 (m, 4H), 6.45 (s, 1H), 6.67 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([CH2:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[Na].[CH2:16]([OH:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH2:16][CH3:17])=[N:8][C:9]([CH2:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(CC)nc1Cl
Reactant: CCO
Agent: [Na]
Product: CCOC(=O)c1cnc(CC)nc1OCC
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution cooled to 0° C. of 64.5 g of 5-ethoxycarbonyl 4-chloro 2-ethyl pyrimidine obtained in the preceding stage, in 200 ml of ethanol, was slowly added a solution of 7.75 g of sodium in 200 ml of ethanol, this being stirred for 15 min. after the addition. Then the solution was acidified to a pH≃3 with hydrochloric ethanol≃6.5 N, and the solvent was evaporated. The residue was diluted in water, extracted with chloroform, dried on sodium sulfate and the solvent evaporated. The residue was distilled and 46.7 g of the expected product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](F)=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)cnc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-chloro-2-fluoro-3-nitropyridine (5 g, 28 mmol) in THF (40 mL) was added morpholine (4 mL, 42 mmol). The reaction was stirred at 0° C. for ten min, at rt for 1 h, and refluxed for four h. The reaction was then cooled to rt, taken up in EtOAc, and washed with satd aq. sodium bicarbonate and brine. The organic layer was dried (magnesium sulfate) and concentrated, affording 4-(5-chloro-3-nitropyridin-2-yl)morpholine as a yellow oil. Mass Spectrum (ESI) m/e=244.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:13][CH:14]([CH2:18][CH2:19][Br:20])[C:15](Cl)=[O:16]>C(OCC)C.O>[Br:13][CH:14]([CH2:18][CH2:19][Br:20])[C:15]([NH:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=1)=[O:16]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(Br)CCBr
Solvent: O
Solvent: CCOCC
Product: O=C(NCc1ccc(C(F)(F)F)cc1)C(Br)CCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of (4-(trifluoromethyl)phenyl)methanamine (3 g, 17 mmol) in diethyl ether (60 mL) under nitrogen at 0° C. was added 2,4-dibromobutanoyl chloride (2.3 mL, 17 mmol) and the reaction mixture was stirred for 1 h at rt. The mixture was then diluted with water and extracted with 200 mL of ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to afford 2,4-dibromo-N-(4-(trifluoromethyl)benzyl)-butanamide (6.5 g, 87%). LCMS (method F) RT 2.01 min, m/z 434.8, 483.8; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39-2.47 (m, 2H) 3.50-3.67 (m, 2H) 4.41 (dd, J=13.05, 6.02 Hz, 2H) 4.59-4.64 (m, 1H) 7.49 (d, J=7.53 Hz, 2H) 7.71 (d, J=8.03 Hz, 2H) 9.06 (s, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8](Cl)[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:14]([NH:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH3:15]>>[CH2:1]([O:5][C:6]1[N:11]=[C:10]([N:16]([CH2:14][CH3:15])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:9]=[C:8]([N:16]([CH2:14][CH3:15])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(Cl)nc(Cl)n1
Reactant: CCNc1cccc(O)c1
Product: CCCCOc1nc(N(CC)c2cccc(O)c2)nc(N(CC)c2cccc(O)c2)n1
Yield: 47 %

Procedure:
This compound was obtained (yield 47%) based on the method described in Production Example 1B using 6-butoxy-2,4-dichloro-1,3,5-triazine instead of the 2,4-dichloro-6-ethyl-1,3,5-triazine, and using 3-ethylaminophenol instead of the 3-aminophenol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:35][CH:36]1[CH:43]2[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:45][CH:37]1[CH2:38]3)[CH2:42]2>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:35][CH:36]1[CH:37]2[CH2:45][CH:41]3[CH2:40][CH:39]([CH2:44][CH:43]1[CH2:42]3)[CH2:38]2)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (ca -78°) solution of 106 g (0.4 mole) of t-butoxycarbonyl-L-phenylalanine (Boc-Phe) and 88 ml (ca. 0.8 mole) of N-methylmorpholine in 300 ml of dichloromethane, stirred over 30 g of 4A molecular sieves, was added dropwise 52.4 ml (ca. 0.4 mole) of isobutyl chloroformate. The mixture was allowed to warm slowly to 5° and then recooled to about -78°. After adding 75 g (0.4 mole) of 2-aminoadamantane, the mixture was allowed to warm to room temperature and to stir overnight. The mixture was clarified by filtration and washed with several portions of 0.5M sodium bisulfate. The organic layer was heated at reflux over activated charcoal, filtered, dried over sodium sulfate, and concentrated in vacuo to dryness. The resultant title compound was used without further purification in subsequent reactions.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([OH:31])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)[S:37][CH:38]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([O:31][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[S:37][CH:38]=2)[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4]
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCC)c2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4cccs4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-thienyl)thiazole (270 mg) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (657 mg, yield: 92%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[C:16]1[N:22]=[C:23]([NH2:25])[S:24][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[C:16]1[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4sc(N)nc4c3c12
Product: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4sc(NC(C)=O)nc4c3c12

Procedure:
100 mg of 2-amino-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester is suspended in 10 ml of acetic anhydride and heated for 15 minutes to 80° C. After cooling, the settled precipitate is filtered off and recrystallized from ethyl acetate. 51 mg of 2-acetamido-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester with a melting point of 208-210° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:23][S-:24].[Na+]>CC(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([S:24][CH3:23])[C:11]=2[CH2:10][CH2:9]1
Reactant: C[S-]
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1nc2c(C)cccc2c2c1CCN2c1ccccc1C
Yield: 49.9 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methyl-2,3-dihydro pyrrolo-[3,2-c]quinoline (1.54 g, 5 mmol) and sodium methanethiolate (1.40 g, 20 mmol) in 2-propanol (25 ml) were heated at 170° in a pressure vessel for 18 hours. The solvent was evaporated, the residue taken up in dichloromethaneand washed with sodium bicarbonate solution. Chromatography (silica gel, dichloromethane) and crystallisation from methanol gave 1-(2-methylphenyl)-4-methylthio-6-methyl-2,3-dihydropyrrolo-[3,2-c]quinoline (0.8 g), m.p. 111°-113°.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)OCC1>>[OH:10][C:14]1([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:15][CH2:16][C:17](=[O:20])[CH2:18][CH2:19]1
Reactant: ClCCc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Product: O=C1CCC(O)(CCc2ccccc2)CC1
Yield: 71 %

Procedure:
(2-chloroethyl)-benzene was reacted with 1,4-dioxa-spiro[4.5]decan-8-one corresponding to the conditions described in Example 24, step 1. The product was purified with 5:1 ether/n-hexane on a silica gel column. Compound (46) was obtained in a yield of 71% theoretical.