Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[CH:4]=1.[Se](=O)=[O:14]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH:10]=[O:14])[S:9][C:5]=2[CH:4]=1
Reactant: O=[Se]=O
Reactant: COc1ccc2nc(C)sc2c1
Solvent: C1COCCO1
Product: COc1ccc2nc(C=O)sc2c1
Yield: 55.5 %

Procedure:
Oxidation of 6-methoxy-2-methylbenzothiazole (10.0 g, 55.9 mmole) with selenium dioxide (6.2 g, 55.9 mmole) in 300 ml dioxane for six hours by the method of Preparation H gave 6.0 g of 6-methoxy-2-formylbenzothiazole after chromatography of the crude product on silica gel, eluting with chloroform. 1H--NMR(CDCl3)ppm(delta): 3.9 (s, 3H), 7.1-7.5 (m, 2H), 8.0-8.3 (m, 1H), 10.1 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([O-:11])([OH:10])=[O:9].[N:12]#[C:13][NH2:14]>C(O)C>[N+:8]([O-:11])([OH:10])=[O:9].[C:2]1([NH:1][C:13]([NH2:14])=[NH:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: Nc1ccccc1
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)Nc1ccccc1
Temperature: 0 °C

Procedure:
Phenyl guanidine nitrate is prepared from a mixture of 12.8 g (0.1 mole) of aniline, 9.0 g of concentrated nitric acid (equivalent to 0.1 mole of HNO3), 12.6 g of a 50 percent aqueous cyanamide solution (equivalent to 0.15 mole of cyanamide) and 100 ml of ethyl alcohol which is heated under reflux for 20 hours. The reaction mixture is then cooled to 0°C for 5 hours and the precipitated product is collected on a filter. The product is purified by recrystallization from ethyl alcohol. The purified white crystalline solid melts at 125°-7°C. The infrared spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1
Product: COc1cccc(N(C)c2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (60% yield). 1H NMR (CDCl3): 7.74-7.76 (m, 1H), 7.57 (ddd, J=8.4, 6.0 and 1.8 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 6.98-7.03 (m, 2H), 6.89 (dd, J=8.1 and 2.4 Hz, 1H), 6.75-6.81 (m, 2H), 3.65 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].S(Cl)([Cl:17])=O>>[ClH:17].[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1ccc(CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: Cl
Product: N=C(N)Nc1ccc(CC(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
21 g of 4-guanidino-phenylacetic acid were added to 200 ml of thionyl chloride that had been cooled to 0° C. After 15 minutes at 0° C, the whole was stirred for 15 minutes at room temperature, the product as precipitated with 500 ml of anhydrous ether, filtered off with suction, washed with anhydrous ether and dried under reduced pressure. 24.7 g of 4-guanidino-phenylacetyl chloride hydrochloride melting at 127° to 130° C were obtained.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[C:15]([O:21][CH3:22])[C:16]([O:19][CH3:20])=[CH:17][CH:18]=1.[C:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)#N.[O:31]1CCCC1>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[C:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[O:31]
Reactant: N#Cc1ccncc1
Reactant: C1CCOC1
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccncc2)cc1OC
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
A hexane solution of butyl lithium (9 mL, 22 mmol, 2.5M) was slowly added to a stirring solution of 4-bromoveratrole (2.9 mL, 20 mmol) in 40 mL of tetrahydrofuran under nitrogen at −70° C. After 15 minutes a solution of 4-cyanopyridine in 12 mL of tetrahydrofuran was added to the reaction mixture and stirring was continued for 45 minutes. The reaction was then allowed to warm to −10° C. and the reaction was carefully quenched with hydrochloric acid (45 mL, 1N). The mixture was stirred for 30 minutes at room temperature. The pH was then adjusted to 12 with 50 mL of a 10% aqueous solution of sodium hydroxide. The mixture was extracted with ether (3×50 mL). The combined ethereal extracts were washed with brine (100 mL) then dried over magnesium sulfate and concentrated in vacuo to a brown solid. The crude product was purified by flash column chromatography (silica gel, 3% methanol/methylene chloride) to afford after vacuum drying (60° C., 1 mm) 1.9 g (39%) of the product: mp 117-118° C.; 1H NMR (CDCl3) δ8.85-8.76 (m, 2 H), 7.60-7.50 (m, 3 H), 7.40-7.30 (m, 1 H), 6.97-6.88 (m, 1 H), 3.98 (s, 3 H), 3.96 (s, 3 H); 13C NMR (CDCl3) δ193.7, 153.9, 150.1, 149.3, 145.2, 128.7, 125.9, 122.6, 111.5, 109.9, 56.1, 56.0; Anal. Calcd for C14H13NO3. Theoretical: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.05; H, 5.39; N, 5.85.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[CH:11]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12]1>>[NH:8]1[C:7]2=[C:2]([NH:16][C:14]([CH:11]3[CH2:13][CH2:12]3)=[O:15])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: Clc1nccc2cc[nH]c12
Reactant: NC(=O)C1CC1
Product: O=C(Nc1nccc2cc[nH]c12)C1CC1
Yield: 7.59 %

Procedure:
N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (Intermediate 7, yield: 7.59%) was synthesized from 7-chloro-1H-pyrrolo[2,3-c]pyridine using cyclopropanamide.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.FC(F)(F)C(O)=O.C(N(CC)CC)C>C(O)C>[F:1][C:2]1[C:3]([NH2:15])=[CH:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:7]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(F)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(N)c(F)n2)CC1

Procedure:
To a suspension of 1-(6-fluoro-5-nitropyridin-2-yl)-4-methylpiperazine.trifluoroacetic acid salt (0.38 g, 1.1 mmol) in ethanol (30 mL) is added triethylamine dropwise with agitation until all of the solid had dissolved. The mixture is then degassed with dry ice and treated with an aqueous slurry of Raney nickel (approx 1.5 mL). After shaking under 50 psi of hydrogen, the reaction mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 2-fluoro-6-(4-methyl-piperazin-1-yl)-pyridin-3-ylamine (contaminated with triethylammonium trifluoroacetate) as a red wine colored solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.C(N(CC)CC)C.ClC(OCC)=O.[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].Cl>CN(C)C=O>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:11]([C:4]1[C:3]2[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][CH:5]=1)=[O:13]
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Reactant: Nc1ccccc1F
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1F)c1c[nH]c2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 64.9 %

Procedure:
To a solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (538 mg, 3 mmol) and triethylamine (0.88 mL, 6.3 mmol) in N,N-dimethylformamide (15 mL) at 0° C. was added ethyl chloroformate (0.57 mL, 6 mmol). After stirring at 0° C. for 45 minutes, 2-fluoroaniline (0.58 mL, 6 mmol) wad added. The mixture was stirred for an additional 45 minutes, then allowed to stir at ambient temperature for 14 hours. The mixture was poured into aqueous 1.2N hydrochloric acid and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. To the residue was added aqueous 1N sodium hydroxide (10 mL) and ethyl alcohol (2 mL) and the mixture heated at reflux for 4.5 hours. After cooling in an ice water bath, the mixture was acidified with aqueous hydrochloric acid, the precipitate collected, rinsed with water and dried. Recrystallization from ethyl alcohol afforded N-(2-fluorophenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 46) (530 mg). mp 238-240° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[C:17]([CH3:30])=[C:16]([CH3:31])[N:15]=1>CN(C)C=O>[ClH:13].[CH3:30][C:17]1[C:18]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[N:19][C:14]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:15][C:16]=1[CH3:31]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Reactant: CCCCN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCNc1nc(C)c(C)c(N2CCc3ccccc3C2)n1
Product: Cl
Yield: 48 %

Procedure:
After butylamine(0.53 ml, 5.4 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 300 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=O)=[CH:10][CH:9]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([C:12]([C:11]2[CH:10]=[CH:9][C:8]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])=[CH:18][CH:17]=2)=[O:14])[CH2:31][CH2:32]1
Reactant: CCOC(=O)c1ccc(N2CCCCC2=O)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCCC4=O)cc3)CC2)c(C)c1
Yield: 56 %

Procedure:
Using ethyl 4-(2-oxopiperidin-1-yl)benzoate (247 mg) and 1-(2,4-dimethylphenyl)piperazine (190 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (219 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.C(OO)(=[O:17])C.C(O)(C)C>C(O)(=O)C>[F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-:17])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)OO
Reactant: Fc1ccccc1Oc1cccnc1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: [O-][n+]1cccc(Oc2ccccc2F)c1
Reaction time: 16 h

Procedure:
A solution of 30 g of 3-(o-fluorophenoxy)pyridine in 50 ml of glacial acetic acid is treated at 35° C. with 33 g of 40% peracetic acid in acetic acid in four portions. The mixture is stirred for 16 hours, refluxed 1 hour and 50 ml of isopropanol is added and the heating continued at 95° C. for 1 hour. The mixture is concentrated at reduced pressure and is dissolved in 300 ml of dichloromethane. The solution is washed with excess 25% sodium hydroxide solution. The dichloromethane solution is dryed over anhydrous MgSO4, filtered and concentrated at reduced pressure. The 3-(o-fluorophenoxy)-pyridine N-oxide crystallizes, mp 89°-95° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[B:11]1(B2OC(C)(C)C(C)(C)O2)[O:15]C(C)(C)C(C)(C)[O:12]1.C([O-])(=O)C.[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[NH2:10][C:4]1[CH:3]=[C:2]([B:11]([OH:15])[OH:12])[CH:7]=[N:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ncc(Br)cc1N
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ncc(B(O)O)cc1N

Procedure:
5-bromo-2-methoxypyridin-3-amine (2 g, 9.85 mmol, commercially available), Bis(pinacolato)diboron (11.82 mmol), potassium acetate (1.4 g) and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) complex with DCM (200 mg, commercially available) was dissolved in dioxane (75 mL) under argon atmosphere. The reaction mixture was refluxed for 8 h. The reaction mixture was cooled, diluted with ethyl acetate (75 mL) and filtered. The filtrate was concentrated. The crude product was purified over silica gel using 0-10% ethyl acetate in petroleum ether to obtain the titled boronic acid derivative.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(OCc2ccccc2)cn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(OCc2ccccc2)cn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 38A, 183 mg, 0.63 mmol) in methylene chloride (6.37 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.35 mL, 0.7 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and then at 25° C. for 30 min. The reaction mixture was then treated with 5-benzyloxy-pyridin-2-ylamine (281 mg, 1.4 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol). The reaction mixture was stirred at 25° C. for 16 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded N-(5-benzyloxy-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (150 mg, 50.0%) as a yellow solid: mp 47-49° C.; EI-HRMS m/e calcd for C26H26Cl2N2O2 (M+) 469.1449, found 469.1455.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.Cl.O1CCOCC1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:15])[CH:11]=[N:10][C:9]=1[Cl:17]
Reactant: C1COCCN1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(c1cnc(Cl)c(Cl)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid (5.76 g; 30.0 mmol) and 4M hydrogen chloride in dioxane (7.5 mL; 30 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2×15 mL) and added to a solution of morpholine (3.1 mL; 36.0 mmol) and triethylamine (10.0 mL; 72 mmol) in DCM (150 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, and the residue partitioned between water (75 mL) and ethyl acetate (100 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (7.1 g).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[NH:18][C:19](=[O:25])[CH2:20][C:21]([F:24])([F:23])[F:22])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:22][C:21]([F:23])([F:24])[CH2:20][C:19]([NH:18][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=1[CH2:9][OH:8])=[O:25]
Reactant: COc1ccc(NC(=O)CC(F)(F)F)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)CC(F)(F)F)c(CO)c1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-((tert-butyldimethylsilyloxy)methyl)-4-methoxyphenyl)-3,3,3-trifluoropropanamide (20.0 g) in anhydrous THF (200 mL) was added a solution of TBAF (16.6 g, 63.6 mmol) in anhydrous THF (60 mL). The mixture was stirred at 35° C. for 30 minutes. The mixture was quenched with ice-water. An aqueous/EtOAc workup was followed by removal of volatiles in vacuo. The crude product was purified by column chromatography on silica gel (PE/EtOAc=1/2) to give the desired product. 1H NMR (CDCl3 400 MHz): δ 8.60 (brs, 1H), 7.82 (d, J=8.8 Hz, 1H), 6.85 (dd, J=9.2, 3.2 Hz, 1H), 6.75 (d, J=2.8 Hz, 1H), 4.65 (s, 2H), 3.80 (s, 3H), 3.23 (q, J=10.4 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([S:17]([CH3:20])(=[O:19])=[O:18])C(OCC)=O)=[O:4].[Cl-].[Na+].C(=O)=O>CCOCC.O.CS(C)=O>[CH3:20][S:17]([CH:11]([CH2:21][CH2:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])(=[O:18])=[O:19]
Reactant: CCCCCC(CCCC(CC#CCCCC(=O)OC)(C(=O)OCC)S(C)(=O)=O)OC(C)=O
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCCCCC(CCCC(CC#CCCCC(=O)OC)S(C)(=O)=O)OC(C)=O

Procedure:
A solution of ethyl 2-(6-methoxycarbonyl-2-hexyn-1yl)-2-(4-acetoxynonyl)-2(methylsulfonyl)-acetate (48.8 g., 0.1 mole), water (3.6 g., 0.2 mole), and sodium chloride (6.5 g., 0.11 mole) in 120 ml. of dimethyl sulfoxide is heated at 130°-150° C. for 6 hours until evolution of carbon dioxide is completed. The mixture is cooled, treated with 400 ml. of water and the oily product taken up in ether, washed with water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a yellow viscous oil.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17]Br.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1
Reactant: c1ccc(-c2nccc3ccccc23)cc1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1cnc(-c2ccccc2)c2ccccc12
Yield: 41.2 %

Procedure:
20.5 g of 1-phenylisoquinoline are dissolved in 100 ml of carbon tetrachloride, and 16 g of bromine are added at room temperature. The temperature is raised slowly and the mixture is kept under reflux for 1 hour. 7.9 g of pyridine in 10 ml of carbon tetrachloride are added dropwise to the boiling reaction mixture in the course of 2 hours, and the mixture is then heated at reflux temperature for a further 18 hours. The reaction solution is decanted off from the resinous precipitate and is concentrated, and the residue is crystallized from diisopropyl ether. 11.7 g of 4-bromo-1-phenylisoquinoline of melting point 123°-125° C. are obtained. 0.7 g of 4-bromo-1-phenylisoquinoline, 0.45 g of copper cyanide and 10 ml of dimethylformamide are heated at 160° C. for 6 hours. The reaction solution is decanted off, diluted with methylene chloride and washed with water. 0.75 g of crude product are isolated from the methylene chloride phase, and 0.2 g of 4-cyano-1-phenylisoquinoline of melting point 138°-140° is obtained from this crude product by column chromatography over silica gel using a 98:2 mixture of chloroform and ethyl acetate. 0.2 g of 4-cyano-1-phenylisoquinoline is heated with 10 ml of 20% strength sodium hydroxide solution at 100° C. for 4 hours. The solution is cooled and acidified with acetic acid. The precipitate is filtered off and dried. 0.18 g of 1-phenylisoquinoline-4-carboxylic acid of melting point 215°-217° is isolated.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:79])[NH:12][C@@H:13]([CH:76]([CH3:78])[CH3:77])[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]3[CH2:36][CH2:35][C@H:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43]5[NH:47][C:46]([C@@H:48]6[CH2:52][CH2:51][CH2:50][N:49]6[C:53](=[O:63])[C@@H:54]([NH:58][C:59]([O:61][CH3:62])=[O:60])[CH:55]([CH3:57])[CH3:56])=[N:45]C=5)=[CH:39][CH:38]=4)[N:33]3[C:64]3[CH:69]=[CH:68][C:67]([CH:70]4[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]4)=[CH:66][CH:65]=3)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:15].Cl[CH2:81][Cl:82]>>[CH3:9][O:10][C:11](=[O:79])[NH:12][C@@H:13]([CH:76]([CH3:78])[CH3:77])[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]3[CH2:36][CH2:35][C@H:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43]5[NH:47][C:46]([C@@H:48]6[CH2:52][CH2:51][CH2:50][N:49]6[C:53](=[O:63])[C@@H:54]([NH:58][C:59]([O:61][CH3:62])=[O:60])[CH:55]([CH3:57])[CH3:56])=[N:45][C:81]=5[Cl:82])=[CH:39][CH:38]=4)[N:33]3[C:64]3[CH:69]=[CH:68][C:67]([CH:70]4[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]4)=[CH:66][CH:65]=3)=[CH:28][CH:27]=2)=[C:24]([Cl:1])[N:25]=1)=[O:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ClCCl
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc([C@H]3CC[C@H](c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)N3c3ccc(C4CCCCC4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(Cl)c(-c2ccc([C@H]3CC[C@H](c4ccc(-c5[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)nc5Cl)cc4)N3c3ccc(C4CCCCC4)cc3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 13 %

Procedure:
N-Chlorosuccinimide (0.046 g, 0.342 mmol) was added to a solution of the product from Example 128 (0.1435 g, 0.149 mmol) in dichloromethane (7 mL) and stirred at ambient temperature for 17 hours. The reaction was diluted with dichloromethane and washed with sat aq NaHCO3 (2×) and concentrated. The residue was purified by flash chromatography (silica gel, MeOH/dichloromethane) then by prep HPLC to afford the title compound (20.4 mg, 13%). 1H NMR (free base) (400 MHz, DMSO-D6) δ 0.94-0.73 (m, 12H), 1.39-0.99 (m, 8H), 1.75-1.41 (m, 6H), 2.27-1.77 (m, 12H), 3.53 (s, 6H), 3.86-3.66 (m, 3H), 4.08-3.96 (m, 2H), 5.11-4.89 (m, 2H), 5.30-5.12 (m, 1H), 5.55-5.33 (m, 1H), 6.21 (d, J=8.7, 1H), 6.88-6.67 (m, 2H), 6.94 (dd, J=4.3, 8.4, 1H), 7.42-7.02 (m, 6H), 7.56-7.42 (m, 3H), 7.61 (t, J=8.5, 1H), 11.68 (d, J=10.7, 1H), 12.49-12.26 (m, 1H). MS (ESI) m/z 1034 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:16][CH3:17])[C:12]=1[O:13][CH2:14][CH3:15])[C:6]([NH:8][NH2:9])=[O:7].[C:18]1([CH:24]=[C:25]2[CH2:29][CH2:28][CH2:27][C:26]2=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH3:17][O:16][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH2:14][CH3:15])[C:6]([NH:8][N:9]=[C:26]1[CH2:27][CH2:28][CH2:29][C:25]1=[CH:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7]
Reactant: O=C1CCCC1=Cc1ccccc1
Reactant: CCOc1c(OC)cc(C(=O)NN)cc1OC
Solvent: CCO
Product: CCOc1c(OC)cc(C(=O)NN=C2CCCC2=Cc2ccccc2)cc1OC
Reaction time: 1 h

Procedure:
A solution of 30.2 g (0.126 moles) of 3,5-dimethoxy-4-ethoxybenzoic acid hydrazide in 250 cm3 of anhydrous ethanol is added to a solution of 21.8 g (0.126 moles) of 2-phenylmethylenecyclopentan-1-one in 50 cm3 of ethanol. The reaction mixture is boiled for one hour, then cooled. The separated crystals are filtered off and dried. Yield: 39.78 g (80.0%). M.p.: 239°-240° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:18][NH:19][CH3:20].O1CCCC1>CN1C(=O)CCC1>[CH3:18][N:19]([CH3:20])[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CN(C)c1ccc([N+](=O)[O-])c(Nc2ccccc2)c1
Yield: 100 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (0.2 g, 0.68 mmol) and 2.0 M dimethylamine in tetrahydrofuran (1.3 ml, 2.7 mmol) in 10 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. N1,N1-dimethyl-4-nitro-N3-phenylbenzene-1,3-diamine (0.17 g, 100%) was obtained by flash column chromatograph (30% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.02 (s, 6H), 6.21 (d, J=2.6 Hz, 1H), 6.23 (s, 1H), 7.22-7.45 (m, 5H), 8.17 (d, J=2.6 Hz, 1H), 9.96 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 40.5, 93.6, 104.8, 124.9, 125.4, 129.5, 130.0, 139.8, 145.9, 155.5.