Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([N:6]=[C:7]=[N:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3]1.C([N:19]=[C:20]=[N:21]C1C=NC=CC=1)(C)(C)C>>[C:20]([N:21]=[C:7]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH:6][C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5]1)#[N:19]
Reactant: CC1(N=C=Nc2cccnc2)CCC1
Reactant: CC(C)(C)N=C=Nc1cccnc1
Product: CC1(NC(=NC#N)Nc2cccnc2)CCC1

Procedure:
By following the procedure of Example 1, but substituting N-1-methylcyclobutyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the desired compound was obtained with a melting point of 210.5°-211.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]([OH:11])=O.[CH:12]1([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:26]=[C:27]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]4[CH3:40])[C:28]4[CH2:33][NH:32][CH2:31][C:29]=4[N:30]=3)=[CH:21][CH:20]=2)=[O:17])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[N:26]=[C:27]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]4[CH3:40])[C:28]4[CH2:33][N:32]([C:9](=[O:11])[CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][C:2]5=[O:1])[CH2:31][C:29]=4[N:30]=3)=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Reactant: O=C(O)CCN1CCCC1=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)CCN1CCCC1=O)C2

Procedure:
Method as example 127 using 3-(2-oxopyrrolidin-1-yl)propanoic acid and (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) as starting materials. Purified by prep HPLC at low pH to afford a white solid. (35.3 mg, 0.066 mmol, 29%).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][CH2:23]I>CN(C)C=O.ClCCl>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:22][CH2:23][O:1][C:2]2[C:3](=[O:14])[C:4]([CH2:12][OH:13])=[CH:5][CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Reactant: COc1ccc(CCI)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CCOc2cc(C(C)C)ccc(CO)c2=O)cc1OC
Temperature: 80 °C
Yield: 10.8 %

Procedure:
A solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (844 mg, 4.35 mmol) in dimethylformamide (5 ml) was stirred while 60% oily sodium hydride (191 mg, 4.78 mg) in small portions were added thereto. Subsequently, 3,4-dimethoxyphenethyl iodide (2.54 mg, 8.70 mmol) was added, then the solution was heated at 80° C. for 7 hours. The solution was diluted with dichloromethane, washed with water and dried over sodium sulfate. After solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (3:2)] to give 169 mg of 2-[2-(3,4-dimethoxyphenyl)ethoxy]-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one as a yellowish brown oil (yield: 11%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Brc1ccccn1
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ccccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 2-bromopyridine
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[C:4]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1.O>CN(C)C=O>[CH3:19][N:18]1[C:14]([C:4]2[C:3](=[O:20])[C:2]([O:1][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:7][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:5]=2)=[CH:15][CH:16]=[N:17]1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cn1nccc1-c1nn(-c2ccccc2)cc(O)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1nn(-c2ccccc2)cc(OCc2ccc3ccccc3n2)c1=O
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of 5-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-1-phenylpyridazin-4(1H)-one (268 mg) in dimethylformamide (10 mL) was added cesium carbonate (782 mg), 2-(chloromethyl)quinoline hydrochloride (236 mg) was added with stirring under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 64 hr. Water was added to the reaction mixture and the mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, washed successively with water, methanol and diisopropyl ether, and dried to give the title compound (226 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([Br:10])[C:3]=1[CH3:11].CS(C)=O.CC(C)([O-])C.[K+].[Cl:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1Cl>C1(C)C=CC=CC=1>[Br:10][C:4]1[C:3]([CH3:11])=[C:2]([CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][C:28]1[CH:27]=[CH:26][C:25]([N+:30]([O-:32])=[O:31])=[CH:24][C:23]=1[Cl:22])[NH2:1]
Reactant: Cc1cc(N)c(C)c(Br)c1O
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc(N)c(C)c(Br)c1Oc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
Into a dry 250 milliliter round bottom flask equipped with a magnetic stirrer and nitrogen inlet was added 4-amino-2-bromo-3,6-dimethylphenol (11.94 grams, 55.3 mmol) prepared in Part B and dry dimethylsulfoxide (118 milliliters). Potassium t-butoxide (7.26 grams, 64.65 mmol) was added portionwise under nitrogen and the mixture was stirred at room temperature for 0.5 hours. Solid 3,4-dichloronitrobenzene (13.33 grams, 70.52 mmol) was then added and the reaction mixture was heated at 50° C. for 48 hours. After cooling the mixture was diluted with toluene and washed successively with saturated NH4Cl solution (3x) and with 5% NaOH solution until the aqueous washes remained colorless. This was followed by washes with water and brine, drying over Na2SO4 and solvent removal under reduced pressure to afford the crude product (9.4 grams) as a dark red-brown oil. Flash column chromatography on 650 grams of silica gel (3:1 hexane:ethyl acetate) afforded pure 3-bromo-4-(2 -chloro-4-nitrophenoxy)-2,5-dimethylaniline (4.7 grams, 12.6 mmol, 23%) as a yellow-brown solid. H'-NMR (CDCl3) 8.42 (d, J=2 Hz, 1H), 8.01 (d,d; J=2, 9 Hz; 1H), 6.55 (d, J=9 Hz, 1H), 6.58 (S, 1H), 3.73 (brS, 2H), 2.28 (S, 3H), 2.06 (S, 3H).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[N:9]([CH2:12][CH:13]1[O:17][CH2:16][CH:15]([S:18][C:19]2[CH:25]([CH3:26])[CH:24]3[N:21]([C:22](=[O:30])[CH:23]3[CH:27]([OH:29])[CH3:28])[C:20]=2[C:31]([OH:33])=[O:32])[CH2:14]1)=[N+]=[N-].C(O[CH:38](OC(C)C)[N:39]([CH3:41])[CH3:40])(C)C>>[CH3:38][N:39]([CH:41]=[N:9][CH2:12][CH:13]1[O:17][CH2:16][CH:15]([S:18][C:19]2[CH:25]([CH3:26])[CH:24]3[N:21]([C:22](=[O:30])[CH:23]3[CH:27]([OH:29])[CH3:28])[C:20]=2[C:31]([OH:33])=[O:32])[CH2:14]1)[CH3:40]
Reactant: CC(C)OC(OC(C)C)N(C)C
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN=CN(C)C)C3)C(C)C12
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
Three ml of sodium phosphate buffer, pH 7, is cooled to 0° C. and 0.052 g of product from Example 46 is added. To this cooled solution is added, dropwise, 159 μl of N,N-dimethylformamide diisopropyl acetal, while maintaining the pH below 8.5. The reaction mixture is stirred at 0° C. for 35 minutes, pH adjusted to 7.0 and freeze-dried. The residue is purified by chromato- graphy (C18 reverse phase tlc plates: 75% aqueous ethyl alcohol) to give 0.031 g of the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][CH:7]=1.[C:14](OC)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[SH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([C:12]2[S:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14](=[O:22])[N:13]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1cccc(-c2cccs2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(-c3cccs3)n2)sc2ccccc12
Yield: 86.8 %

Procedure:
6-(2-Thienyl)-2-pyridinecarbonitrile (0.56 g, 3.0 mmol) and methyl thiosalicylate (0.77 g, 4.6 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 10 hrs. After cooling, the precipitates were collected by filtration and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.84 g, 86%) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:15](O)[CH3:16]>O>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CNc1cccc([N+](=O)[O-])c1
Reactant: CCO
Solvent: O
Product: CCOC(=O)CNc1cccc([N+](=O)[O-])c1

Procedure:
2 g of 3-nitrophenylglycine are heated for 20 hours with stirring at a temperature in the region of 100° C. in 100 cm3 of absolute ethanol containing 20 cm3 of 6.5N hydrochloric ethanol. The suspension is filtered at a temperature in the region of 50° C.; the filtrate is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in water and then extracted with about 100 cm3 of ethyl acetate. The aqueous phase is made alkaline by addition of sodium carbonate until a pH in the region of 10 is obtained. The medium is extracted with ethyl acetate; the combined extracts are washed with aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure (5 kPa) at 40° C. 1 g of ethyl 3-nitrophenylglycinate is obtained in the form of a yellow oil. (Rf=0.38 in a 95/5 by volume mixture of dichloromethane/methanol, on a Merck 60F254R silica plate).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:3]([C:2](=[O:1])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:22][CH:21]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(F)cc1)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of ethyl 3-oxo-3-(4-trifluoromethylphenyl)propionate (38.2 g, 0.147 mol), 4-fluorobenzyl bromide (25 g, 0.13 mol), potassium carbonate (36.6 g, 0.26 mol) and acetonitrile (500 ml) was stirred at 60° C. for 3 hrs. The reaction solution was concentrated under reduced pressure, and water (500 ml) was added. The mixture was extracted with ethyl acetate (500, 200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-10:1, hexane:toluene=1:1) and crystallized from cold hexane to give ethyl 2-((4-fluorophenyl)methyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)propionate (29.5 g, 55%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=3)[C:16]([O:18]CC)=[O:17])[S:10][C:6]=2[C:5]([F:24])=[CH:4][C:3]=1[F:25].[OH-].[Na+]>O.O1CCOCC1>[F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=3)[C:16]([OH:18])=[O:17])[S:10][C:6]=2[C:5]([F:24])=[CH:4][C:3]=1[F:25]
Reactant: CCOC(=O)c1cccc(CCc2nc3c(F)c(F)cc(F)c3s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(CCc2nc3c(F)c(F)cc(F)c3s2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 67.5 %

Procedure:
To a solution of ethyl 3-[2-(4,5,7-trifluorobenzothiazol-2-yl)ethyl]benzoate (133 mg, 0.36 mmol) in a mixture of water (5 ml) and dioxane (5 ml) was added dropwise aqueous 2N sodium hydroxide (2 ml) and the mixture was stirred for 7 hours at ambient temperature. The reaction mixture was diluted with water and then washed with ether. The aqueous layer was acidified with 10% hydrochloric acid and extracted with ethyl acetate. After drying, evaporation of the solvent left crude crystals, which were recrystallized from ether to give 3-[2-(4,5,7-trifluorobenzothiazol-2-yl)ethyl]benzoic acid (82 mg, 68%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Product: COc1nc(Nc2ccc(Cl)cc2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Yield: 15 %

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloroaniline in analogy to example 1c). It was obtained in 15% yield as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1c[nH]c(C(N)=O)c1-c1ccc(N)cc1
Yield: 99.2 %

Procedure:
To a suspension of 0.024 g (0.222 mmol) of 10% palladium-on-charcoal in 63 cm3 of methanol is added, at a temperature in the region of 20° C., 0.331 g (0.956 mmol) of 4-tert-butyloxycarbonylamino-3-(4-nitrophenyl)-1H-pyrrole-2-carboxamide. After hydrogenating for 5 hours in an autoclave under 4 bar of hydrogen, at a temperature in the region of 40° C., the reaction mixture is filtered. The catalyst is rinsed with twice 15 cm3 of methanol and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.3 g of 4-tert-butyloxycarbonylamino-3-(4-aminophenyl)-1H-pyrrole-2-carboxamide in the form of a white solid melting at about 142° C.; EI: m/z=316 M+; m/z=260 [M-tBu]+; m/z=243 [M-OtBu]+; m/z=199 [243-CONH2]+; m/z=57: [tBu]+ base peak.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65](=[O:73])[NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56]([OH:58])=O)=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.Cl.[CH3:76][N:77]1[C@H:82]([CH3:83])[CH2:81][NH:80][CH2:79][C@@H:78]1[CH3:84].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65]([NH:66][S:67]([CH:70]([CH3:71])[CH3:72])(=[O:68])=[O:69])=[O:73])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:51][CH2:52]5)[N:48]=[C:47]([CH:53]([CH3:54])[CH3:55])[C:46]=4[C:56]([N:80]4[CH2:81][C@H:82]([CH3:83])[N:77]([CH3:76])[C@H:78]([CH3:84])[CH2:79]4)=[O:58])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C[C@@H]1CNC[C@H](C)N1C
Reactant: COc1ccc2c(c1)C=C(c1c(C(=O)O)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(c1c(C(=O)N3C[C@@H](C)N(C)[C@@H](C)C3)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reaction time: 2 h
Yield: 28.9 %

Procedure:
HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), (2S,6R)-1,2,6-trimethylpiperazine dihydrochloride (46 mg, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/CH3CN gradient, and concentrated to give the titled compound (31 mg, 0.033 mmol, 29% yield) consistent by LCMS and NMR, with sufficient purity by HPLC.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[N:1][C:2]([C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=1)=[CH:12][N:13]([CH3:15])[CH3:14]
Reactant: CCc1noc(CN)n1
Reactant: COC(OC)N(C)C
Product: CCc1noc(C(=CN(C)C)N=CN(C)C)n1
Temperature: 80 °C
Yield: 72 %

Procedure:
A mixture of 11.5 g of 5-aminomethyl-3-ethyl-1,2,4-oxadiazole and 24 ml of dimethylformamide dimethylacetal is heated to 80° C. for 7 hours; during this process, 10 ml of thus-formed methanol is removed by distillation. After adding another 12 ml of DMF-acetal, the mixture is refluxed for 3 hours, then subjected to fractional distillation. The fraction passing over at 155°-160° C. and 0.03 torr, 1,4-bis(di- methylamino)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-aza1,3-butadiene is obtained in a yield of 72% of theory; nD20 1.5908.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:24]=[C:23]([CH3:25])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19](=O)[NH:20][CH:21]=3)=[C:10]([CH3:26])[CH:9]=2)[N:4]=1.CI.[C:31]([O-:34])([O-])=O.[K+].[K+]>COCCOCCN(CCOCCOC)CCOCCOC.CN(C=O)C>[F:27][C:2]([F:1])([F:28])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH3:26])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[C:31](=[O:34])[N:20]([CH3:21])[CH:19]=[CH:18][CH:17]=3)=[C:23]([CH3:25])[CH:24]=2)[N:4]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(=O)[nH]c1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1cccn(C)c1=O
Yield: 91.7 %

Procedure:
To a solution of 0.95 g (2.41 mmol) of 5-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-2 (1H)-pyridone, 20 drops of TDA-1, and 0.5 ml of methyl iodide in 50 ml of dry DMF was added 0.96 g (3 eq) of milled K2CO3. The mixture was filtered and concentrated in vacuo to afford 0.9 g (91.8%) of 3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-1-methyl-2-pyridone, as a white solid, which was recrystallized from isopropyl acetate to yield a white solid, 143°-146° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C1C(=O)N([I:20])C(=O)C1>CN(C=O)C.CCOC(C)=O>[I:20][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
5-nitro-1H-indazole (2 g, 12.26 mmol) was taken up in DMF (40 mL) and NIS (5.52 g, 24.52 mmol) was added. The reaction was stirred at room temperature for 72 h. The reaction mixture was diluted with EtOAc and washed with saturated sodium bisulfite solution, water, and then 2× with brine. The organic layer was dried over Na2SO4, filtered and concentrated to give 3-iodo-5-nitro-1H-indazole (3.4 g) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:11]=[C:10]([C:12]2[C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[C:19]([Br:29])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:9]=[C:8]([Br:30])[C:7]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:5][C:6]1[CH:11]=[C:10]([C:12]2[C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[C:19]([Br:29])=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:9]=[C:8]([Br:30])[C:7]=1[O:31][CH2:2][C:3]#[N:4]
Reactant: N#CCBr
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reaction time: 2.5 h
Yield: 96.1 %

Procedure:
Bromoacetonitrile (0.25 mL, 3.56 mmol) was added to a room temperature, stirred suspension of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (1.0 g, 1.78 mmol) and potassium carbonate (0.615 g, 4.45 mmol) in DMF (5 mL). After 2.5 h, the reaction mixture was added to water, filtered, washed with water and triturated with petroleum ether. The solid was dried in vacuo at 80° C. to provide the title compound as a white solid (1.03 g, 96%): NMR (DMSO-d6); δ8.29 (d, J=8 Hz, 1 H), 8.08 (d, J=8 Hz, 1 H), 7.92 (s, 2 H), 7.80 (ddd, J=8, 7, 1 Hz, 1 H), 7.65-7.51 (m, 3 H), 7.27 (ddd, J=8, 7, 1 Hz, 1 H), 6.68 (d, J=8 Hz, 1 H), 5.36 (s, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 599, 601, 603, 605; Anal. Calc. for C24H12Br3NOS: C, 47.87, H, 2.01, N, 2.33. Found: C, 47.83, H, 1.92, N, 2.32.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21](Cl)=[O:22])[CH:8]=2)[CH:3]=1.[CH2:24]([NH2:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>O1CCCC1>[OH:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([NH:40][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:22])[CH:8]=2)[CH:3]=1
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=C(Cl)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCNC(=O)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Temperature: 30 °C
Yield: 35.9 %

Procedure:
A dispersion of 6.5 g of 2-hydroxy-3-phenylaminocarbonyl-6-chlorocarbonylnaphthalene in 20.0 g of dry tetrahydrofuran was added with 9.2 g of n-hexadecylamine solution in 30 g of dry tetrahydrofuran and reacted under reflux for 12 hours. To the reaction mixture, 30 g of water was added and the precipitates were collected by filtration, washed with water and thus obtained crystal was washed with 30 g of methanol under reflux. The obtained mixture was cooled to 30° C. and filtrated, washed with methanol and dried to provide 3.8 g of 2-hydroxy-3-phenylaminocarbonyl-6-n-hexadecylaminocarbonyl naphthalene (decomposition point: 257.2° C.).