Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: COc1cccc(CN)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: COc1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-methoxybenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. 1H NMR (500 MHz, CDCl3): δ 0.60 (br s, 1H); 8.44 (br s, 1H); 8.08 (br s, 1H); 7.86 (d, J=8.5 Hz, 1H); 7.3-7.5 (m, 3H); 7.02 (d, J=7.6 Hz; 1H); 6.98 (s, 1H); 6.85 (m, 2H); 5.86 (br s, 1H); 4.73 (d, J=5.7 Hz, 2H); 3.82 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:12][C:13]2[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][CH:16]=[CH:17][CH:18]=2)[S:8][C:9]=1[CH2:10]O)([CH3:4])([CH3:3])[CH3:2].[CH2:30]([NH:34][CH3:35])[CH:31]([CH3:33])[CH3:32]>>[C:1]([C:5]1[N:6]=[C:7]([NH:12][C:13]2[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][CH:16]=[CH:17][CH:18]=2)[S:8][C:9]=1[CH2:10][N:34]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH3:35])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)C
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(C)(C)C)c(CO)s1
Product: CC(C)CN(C)Cc1sc(Nc2cccnc2Oc2ccccc2C(C)(C)C)nc1C(C)(C)C

Procedure:
Example A161 was prepared from (4-tert-butyl-2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)thiazol-5-yl)methanol (Example 252) and isobutyl methyl amine according to the procedure described for Example 272. (M+H)+=493.2.
Reaction SMILES: COC1N=CC(C2N=C(C)NC=2CCCC[N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])=CC=1.COC1C=CC(C2N=C(C)NC=2)=CN=1.C(=O)([O-])[O-].[K+].[K+].BrCCCCN1C(=O)C2=CC=CC=C2C1=O>CN(C=O)C>[C:19]1(=[O:28])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:27])[NH:18]1
Reactant: COc1ccc(-c2nc(C)[nH]c2CCCCN2C(=O)c3ccccc3C2=O)cn1
Agent: COc1ccc(-c2c[nH]c(C)n2)cn1
Agent: O=C([O-])[O-]
Agent: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
2-{4-[4-(6-methoxy(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione. To a solution of 2-methoxy-5-(2-methylimidazol-4-yl)pyridine (5.0 g, 26.4 mmoles) in DMF (100 ml) was added potassium carbonate (18.3 g, 132 mmoles) and N-(4-bromobutyl)phthalimide (8.97 g, 31.7 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 72 hours. The reaction was filtered and the resulting clear solution was dumped onto ice (1 L). The precipitate was filtered and rinsed with water (2×200 ml) and was pumped on for 1 hour. The material was than rinsed with diethyl ether (7×200 ml) and than was pumped on to yield to yield 2-14-[4-(6-methoxy(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione (4.1 g, 48%). MH+(391)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C(Cl)Cl>O1CCOCC1>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:27]([CH3:26])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: CNc1ccccc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CN(c1ccccc1)c1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1
Yield: 64 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (92 mg, 0.25 mmol) and N-methylaniline (67 mg, 0.625 mmol) in dioxane (5 mL) was heated under reflux for 1 hr and cooled. Dilution with water gave a precipitate, which was collected and dried. Chromatography on SiO2 eluting with CH2Cl2 gave 70 mg (64% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-N-phenyl-1,3,5-triazin-2-amine: mp (hexanes) 160-162° C.; 1H NMR (CDCl3) δ 8.04 (m, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.45-7.06 (m, 7H), 3.91 (m, 4H), 3.81 (m, 4H), 3.56 (s, 3H); Anal. Calc. for C22H21F2N7O: C, 60.4; H, 4.8; N, 22.4. Found: C, 60.2; H, 5.0; N, 22.5%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:30]>C(O)C.O1CCCC1>[Na+:30].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=3)[O:17][CH2:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C([O-])CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the ester of Example 5, Step 2, (15 g) in ethanol (200 ml) and tetrahydrofuran (200 ml) was added 2N NaOH (35 ml). The reaction was stirred at room temperature overnight and the product filtered The solid was stirred for 2 hours at room temperature in ethanol (100 ml) and filtered to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:20])[N:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:13])[N:8]([CH2:10][O:11][CH3:12])[CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[C:5](=[O:20])[N:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:13])[N:8]([CH2:10][O:11][CH3:12])[CH:9]=1
Reactant: CCOC(=O)Cn1c(=O)c([N+](=O)[O-])cn(COC)c1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)c(N)cn(COC)c1=O

Procedure:
A stirred solution of the compound of Example 42 (10.0 g, 35 mmole) in ethanol (100 mL) is hydrogenated over 10% Pd/C (1.00 g) for 8 hours under balloon pressure. Celite is added, and the reaction mixture is filtered through a pad of celite, using ethyl acetate to wash. The solvent is removed in vacuo to give crude ethyl 5-amino-1-methoxymethyl-uracilylacetate.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5](Cl)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:6](Cl)=[N:7][C:8]=1[C:9]#[N:10])#[N:2].[CH2:20]([NH2:22])[CH3:21]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:22][CH2:20][CH3:21])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: CCN
Reactant: N#CC1=C(C#N)NC(Cl)(c2cccc(F)c2)C(Cl)=N1
Solvent: Cc1ccccc1
Product: CCNc1nc(C#N)c(C#N)nc1-c1cccc(F)c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
2,3-Dicyano-5-chloro-6-chloro-6-(m-fluorophenyl)pyrazine (1.00 g; 0.0039 mole) was dissolved in 30 ml of toluene. The solution was cooled to -5° C., and 0.65 g of a 70% aqueous solution of ethylamine was added dropwise. The mixture was stirred at -5° to 0° C. for 30 minutes. The reaction mixture was worked up in the same way as in Example 13, and recrystallized from ethanol to afford 0.63 g (yield 61%) of 2,3-dicyano-5-ethylamino-6-(m-fluorophenyl)pyrazine.
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]([C:9]1([CH:17]=[O:18])[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH:10]1[CH3:16])([CH3:8])[CH3:7]>O1CCCC1>[CH:6]([C:9]1([CH2:17][OH:18])[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH:10]1[CH3:16])([CH3:8])[CH3:7]
Reactant: CC1=CC(C)C(C=O)(C(C)C)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1=CC(C)C(CO)(C(C)C)CC1
Reaction time: 3 h

Procedure:
Isopropylmagnesium chloride ((CH3)2HCMgCl) in tetrahydrofuran (THF) (1.6 L, 3.2 mol) was loaded into a flame-dried 5 L round bottom flask. Additional THF (1 L) was added. 1-Isopropyl-2,4-dimethyl-cyclohex-3-enecarbaldehyde (obtained as detailed above) was then fed for over 2 hours at 0° C. under nitrogen. The reaction mixture was aged at 0° C. for another 3 hours and then quenched by pouring the reaction mixture onto a sulfuric acid solution (10%) on crushed ice. The organic layer was separated, washed with sodium carbonate solution, and distilled to provide (1-isopropyl-2,4-dimethyl-cyclohex-3-enyl)-methanol.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]1([CH2:21][C:22]([Cl:24])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:24].[C:9]1([N:6]2[CH:7]=[CH:8][C:3](=[N:2][C:22](=[O:23])[CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[N:5]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Product: O=C(Cc1ccccc1)N=c1ccn(-c2ccccc2)nc1
Yield: 41 %

Procedure:
6.0 g (28.9 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 50 ml of phenylacetyl chloride were kept at 120° C. for 6 hours, while stirring. The mixture was cooled and then evaporated down, and the residue was treated with methanol/methyl tert.-butyl ether. The solid was filtered off under suction and recrystallized first from ethanol and then from ethanol/acetone with the addition of active charcoal. 3.9 g (41% of theory) of 1,4-dihydro-1-phenyl-4-[(phenylacetyl)-imino]-pyridazine hydrochloride were isolated as pale beige crystals of melting point 208°-210° C.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:15](=[O:16])[NH:14][C:13](=[O:17])[O:12][C:11]1=[O:18]>>[CH3:9][N:10]1[C:15](=[O:16])[N:14]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:17])[O:12][C:11]1=[O:18]
Reactant: ClCc1ccccc1
Reactant: Cn1c(=O)[nH]c(=O)oc1=O
Product: Cn1c(=O)oc(=O)n(Cc2ccccc2)c1=O
Yield: 83 %

Procedure:
The process described in example 1 is carried out. 15.2 g of benzyl chloride (0.12 mole) are added to the obtained solution of the salt of 3-methyl-1,3,5-oxadiazine-2,4,6-trione. After 3 hours of reaction at a temperature of 60° C., one obtains 19.4 g of 3-methyl-5-benzyl-1,3,5oxadiazine-2,4,6-trione (yield: 83%) which is an asymmetrical disubstituted 1,3,5-oxadiazine trione of the formula (III).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[C:22]([Br:25])[CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Solvent: ClCCl
Product: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a 2 dram vial was added 0.20 g (0.6 mmol) 4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine, 6.0 mL CH2Cl2, and 104 mg (0.6 mmol) N-bromosuccinimide. The reaction was stirred for 30 min at rt and then quenched with 1 M Na2SO3. The organic layer was separated, dried, and concentrated in vacuo. The deep red product was purified by MPLC to give 0.059 g (24% yield) of a clear, tacky liquid. MS (APCI): 419 [M+H]+.
Reaction SMILES: [N:1]([C:3]1[C:4]([NH2:16])=[N:5][C:6]([NH2:15])=[N:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:14])[CH2:12][CH3:13])=O.[ClH:17]>C(O)C.[Pd]>[ClH:17].[ClH:17].[CH3:14][CH:11]([CH2:12][CH3:13])[CH2:10][O:9][C:8]1[N:7]=[C:6]([NH2:15])[N:5]=[C:4]([NH2:16])[C:3]=1[NH2:1]
Reactant: CCC(C)COc1nc(N)nc(N)c1N=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCC(C)COc1nc(N)nc(N)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a solution of 19.0 g (0.084 mol) 5-nitroso-2,4-diamino-6-(2-methylbutoxy)pyrimidine from step 3.2 in 400 ml ethanol was added 4.0 g (0.04 mol %) palladium on charcoal (5%). The mixture was shaken at room temperature for 18 h under an atmosphere of hydrogen at 1 bar. The reaction mixture was then poured into 150 ml dilute hydrochloric acid (0.30 mol), the catalyst was filtered off and the filtrate was concentrated almost to dryness. The precipitated crystals were filtered off with suction and washed with tert-butyl methyl ether. 6-(2-Methylbutoxy)-2,4,5-pyrimidinetriamine dihydrochloride (19.5 g, 81%) was obtained as light yellow crystals.
Reaction SMILES: F[C:2]1[C:12]([F:13])=[CH:11][C:10]([I:14])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>Cl.ClCCl>[F:13][C:12]1[C:2]([NH:15][CH:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)=[C:3]([CH:9]=[C:10]([I:14])[CH:11]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CN(C)C(=O)c1cc(I)cc(F)c1F
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(I)cc(F)c1NC1CCC(O)CC1
Yield: 90 %

Procedure:
2,3-Difluoro-5-iodo-N,N-dimethyl-benzamide (2.36 g, 7.6 mmol) and trans-4-amino-cyclohexanol (3.5 g, 30 mmol) were stirred at 120° C. for 5 hrs. The resulting solid was dissolved in 1 N hydrochloric acid and dichloromethane. The aqueous layer was extracted with dichloromethane twice. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated to give 2.8 g (6.84 mmol, 91%) of 3-fluoro-2-(4-hydroxy-cyclohexylamino)-5-iodo-N,N-dimethyl-benzamide as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.45 (dd, J1=12 Hz, J2=2 Hz, 1H), 7.15 (s, 1H), 4.57 (dd, J1=10 Hz, J2=3 Hz, 1H), 4.50 (d, J=4.5 Hz, 1H), 3.33 (m, 1H), 3.02 (m, 1H), 2.94 (bs, 3H), 2.81 (bs, 3H), 1.74 (m, 4H), 1.04-1.24 (m, 4H); MS: m/z 407 [MH+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([CH3:38])[C:36]=1O)[C:32]#[N:33]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][C:36]3[C:35]([CH3:38])=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=3[CH3:28])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: Cc1cc(C#N)cc(C)c1O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 22 %

Procedure:
To an ice-cold solution of 0.38 g (0.97 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), 0.157 g (1.07 mmol) 3,5-dimethyl-4-hydroxybenzonitrile (commercially available) and 0.29 ml (1.17 mmol) tri-N-butylposphine in 8 ml tetrahydrofuran, 0.20 g (1.17 mmol) N′N′N′N-tetramethylazodicarboxylate were added in one portion. After 48 h stirring at RT another 0.29 ml (1.17 mmol) tri-N-butylposphine and 0.2 g (1.17 mmol) N′N′N′N-tetramethylazodicarboxylate were added. The reaction mixture was stirred at RT for another 5 days, silica gel was added and the suspension evaporated to dryness. The residue was chromatographed three times using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane and tert-butyl methyl ether (100:0 to 60:40) to give the desired compound as a light yellow solid (22%). MS (Turbo Spray): m/z=520.3 [M+H].
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)(=O)C>[C:20]([NH:4][CH2:1][C:2]#[CH:3])([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C#CCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of propargylamine (20 g) and triethylamine (60.7 mL) in ethyl acetate (500 mL) was added benzyloxycarbonyl chloride (71.7 g) slowly while maintaining the reaction temperature between −5° C. and +5° C. The mixture was then stirred at room temperature overnight. The mixture was washed sequentially with 1.5 M HCl (200 mL), 5% NaHCO3 in water (200 mL), and saturated aqueous sodium chloride (100 mL). The solvent was switched to hexane while the desired product precipitated as colorless crystals (60.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH:12]([CH3:16])[N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1Cc2[nH]c3ccc(Cl)cc3c2CN1C
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC1Cc2c(c3cc(Cl)ccc3n2CCc2ccc(C(F)(F)F)nc2)CN1C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2,3-dimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]2[N:20]=[CH:19][CH:18]=[C:17]([CH3:23])[C:16]=2[C:15](=[O:24])[CH2:14]1.C(=O)([O-])O.[Na+]>ClCCl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]2[N:20]=[CH:19][CH:18]=[C:17]([CH3:23])[C:16]=2[C:15](=[O:24])[CH2:14]1
Reactant: COc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1O)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
To a solution of boron tribromide (0.96 g) in dichloromethane (30 ml) was added dropwise at −78° C. a solution of 7-(2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.33 g) in dichloromethane (1 ml), and the mixture was gradually warmed to room temperature and stirred at room temperature for 1.5 hours. To the mixture were added carefully ice and sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 7-(2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.23 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(=O)[nH]ccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]ccc2cc(O[C@H]3CCCNC3)ccc12
Yield: 51.2 %

Procedure:
(S)-3-(Oxo-1,2-dihydroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (1.25 g, 3.6 mmol) was mixed with dichloromethane (30 ml) and trifluoroacetic acid (10 ml) at ambient temperature for 15 minutes. Volatiles were removed under reduced pressure and excess trifluoroacetic acid was azeotroped with toluene. The residue was dissolved in methanol and purified using an SCX cartridge. Concentration gave (S)-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one (450 mg, 51%), El-MS: m/z=245.4 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OC(=O)C)(=O)C>CCOCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][C:12](=[O:14])[O:18][C:16](=[O:17])[CH2:15]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)O1
Temperature: 80 °C
Yield: 70 %

Procedure:
A flask was charged with 20.0 g (79.0 mmol) of 3-(4-nitro-phenyl)-pentanedioic acid (as prepared in the previous step) and 22.4 mL (237 mmol) of acetic anhydride. The mixture was heated to 80° C. for 1 h, cooled to RT, and treated slowly with ether until the product began to precipitate. After allowing the solid to fully precipitate, the solid was filtered, washed with ether, and air-dried to afford 13.0 g (70%) of the title compound as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 8.28 (d, 2H, J=8.8 Hz), 7.41 (d, 2H, J=8.8 Hz), 3.64-3.53 (m, 1H), 3.22-3.13 (m, 2H), 2.96-2.85 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1(CC)[O:7]C(=O)CC(=O)[O:3]1.[CH:12](=O)[C:13]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[C:15]([O:16][CH3:17])[CH:14]=1.C(O)=O>C(N(CC)CC)C>[CH3:17][O:16][C:15]1[CH:14]=[C:13]([CH2:12][CH2:1][C:2]([OH:7])=[O:3])[CH:22]=[CH:21][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCC1(C)OC(=O)CC(=O)O1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC
Temperature: 95 °C

Procedure:
3.95 g (0.025 mol) of 2-methyl-2-ethyl-1,3-dioxane-4,6-dione and 4.15 g (0.025 mol) of veratraldehyde were weighed in to 25 ml of the mixture of formic acid and triethylamine prepared as described in Example 1. The reaction mixture was heated to 95° C. during 1 hour and maintained at the same temperature for 2 hours, then Example 1 was followed.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Brc1cnc2ccc(N3CCOCC3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and morpholine according to general procedure 1 providing the amino compound (235 mg, 85%) as a yellow solid: Rf=0.79 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=9.9 Hz, 1H), 7.53 (s, 1H), 6.81 (d, J=9.9 Hz, 1H), 3.86 (t, J=5.0 Hz, 4H), 3.55 (t, J=4.8 Hz, 4H); ES-MS: (M+H)=283, 285 m/z.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:21]3[C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:23])[C:12]=3[C:11](Br)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([NH:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH:1]1([NH:7][C:8]2[C:21]3[C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:23])[C:12]=3[C:11]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([NH:30][C:31]([CH3:32])=[O:33])=[CH:34][CH:35]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)c2c(NC3CCCCC3)ccc(Br)c21
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Nc2ccc(NC3CCCCC3)c3c2C(=O)c2ccccc2C3=O)cc1

Procedure:
1-Nitroanthraquinone is refluxed with an excess of cyclohexylamine in o-dichlorobenzene to yield 1-cyclohexylamino anthraquinone which is further brominated in aqueous pyridine to yield the corresponding 1-cyclohexylamino-4-bromoanthraquinone. This compound is further condensed with p-amino acetanilide to yield 1-cyclohexylamino-4-(p-acetaminoanilino)anthraquinone as a bright green pleochroic dye having an optical order parameter 0.7.