Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[C:12](O)(=[O:16])[C:13](O)=[O:14].C(O)C>Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]2[C:3]=1[NH:11][C:12](=[O:16])[C:13](=[O:14])[NH:10]2
Reactant: Nc1cc(F)c(F)c(F)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2cc(F)c(F)c(F)c2[nH]c1=O
Reaction time: 8 h
Yield: 4 %

Procedure:
To a brown solution of 3,4,5-trifluoro-1,2-phenylenediamine (285 mg, 1.75 mmol) in aqueous 2N HCl (10 mL) is added oxalic acid (221 mg, 1.75 mmol). The brown mixture is brought to reflux and stirred under N2 overnight. The mixture is filtered to yield 139 mg (37%) of crude title compound. An analytical sample is prepared by dissolving 42 mg of this brown powder in 2.5 mL boiling ethanol. Upon cooling, brown, rod-like, crystals are formed, which are filtered and dried in vacuo to yield 15 mg (36%) of pure title compound: 1H NMR (DMSO-d6), 6.91 (m, 1H), 12.02 (s, 1H), 12.19 (s, 1H); analysis calculated for C8H3F3N2O2 : C, 44.46; H, 1.40; N, 12.96. Found: C, 44.42; H, 1.16; N, 12.76.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[BH4-].[Na+]>CC(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 174.1 %

Procedure:
To a suspension of (E)-1-chloro-4-(4-(2-nitrovinyl)phenoxy)-2-(trifluoromethyl)benzene (13 g, 43.2 mmol) and silica gel (120 g, 100-200 Mesh) in i-PrOH (155 mL) and CHCl3 (465 mL), was added NaBH4 (13.65 g, 361 mmol) portionwise. The reaction mixture was stirred overnight at rt, filtered, and washed with DCM (1 L). The organic phase was washed with sat. NaHCO3 (200 mL), then brine, and dried over anhydrous Na2SO4 and concentrated to afford the title compound as a brown liquid (26 g, 50% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])C1C=CC=CC=1.CS(O[C@@H](C1C=C2C(C=NN2CC2C=CC=CC=2)=CC=1)COS(C)(=O)=O)(=O)=O.CN1C2C(=CC=CC=2)CC1=O>>[CH2:28]([N:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([C@H:17]3[C@@:10]4([C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:8]([CH3:1])[C:9]4=[O:35])[CH2:18]3)[CH:27]=2)[CH:23]=[N:24]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Agent: CN1C(=O)Cc2ccccc21
Agent: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)c1ccc2cnn(Cc3ccccc3)c2c1
Product: CN1C(=O)[C@@]2(C[C@H]2c2ccc3cnn(Cc4ccccc4)c3c2)c2ccccc21
Yield: 84 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (6.70 g, 15.8 mmol) and 1-methylindolin-2-one (2.33 g, 15.8 mmol). Purification via column chromatography (silica gel, 25-50% EtOAc in hexane) yielded the title compound as a pale-orange crystalline solid (5.01 g, 84%); 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.30-7.25 (m, 3H), 7.18 (s, 1H), 7.13-7.10 (m, 3H), 6.92 (d, J=8.6 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.55 (t, J=7.0 Hz, 1H), 5.76 (d, J=7.2 Hz, 1H), 5.63-5.49 (m, 2H), 3.41 (t, J=8.8 Hz, 1H), 3.33 (s, 3H), 2.22-2.18 (m, 1H), 2.00-1.96 (m, 1H); MS ESI 380.2 [M+H]+, calcd for [C25H21N3O+H]+ 380.18.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:35])[C@@H:18]([NH:27]C(=O)OC(C)(C)C)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)[C:3]1=[O:36].Cl.[Cl:39][Si](C)(C)C.CO>C(OCC)C>[ClH:39].[NH2:27][C@@H:18]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:37])([CH3:1])[C:3]2=[O:36])[CH2:16][CH2:15]1)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N1CCC(N2C(=O)C(C)(C)c3ccccc32)CC1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC1(C)C(=O)N(C2CCN(C(=O)[C@@H](N)CCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of (S)-tert-butyl 1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-ylcarbamate (2.79 g, 5.52 mmol, EXAMPLE 1, Step 3) and 1 mol/L hydrochloride in diethyl ether (25 mL) was stirred at room temperature. After 4 h, a mixture of chlorotrimethylsilane (2 mL) and methanol (4 mL) was added to the reaction suspension. The whole mixture changed to a clear solution and was stirred for 3 h. The mixture was concentrated in vacuo and the residue was diluted with diethyl ether and re-concentrated to remove methanol completely. The obtained solid was washed with diethyl ether to give the title compound (2.05 g, 84%).
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:23]1([CH3:30])[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][CH:24]=1.OS(O)(=O)=O.[OH-].[Na+]>C(O)(=O)C.O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:2]2([C:25]3[CH:26]=[CH:27][C:28]([OH:29])=[C:23]([CH3:30])[CH:24]=3)[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][CH:19]=1
Reactant: COc1ccc(C2(O)c3ccccc3-c3ccccc32)cc1
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2(c3ccc(O)c(C)c3)c3ccccc3-c3ccccc32)cc1
Reaction time: 0.01 h
Yield: 95.2 %

Procedure:
4-Bromoanisole (46.7 g) was added dropwise to a stirred mixture of magnesium (6.0 g) in dry THF (250 mL). When all the magnesium had dissolved, 9-fluorene (40.0 g) in THF (400 mL) was added dropwise. The mixture was then stirred at room temperature for 3 hours and quenched with saturated ammonium chloride solution. The excess solvent was evaporated in vacuo and the residue extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered, evaporated and recrystallized from hexane/ether to give 9-hydroxy-9-(4-methoxyphenyl)fluorene as a solid (48.2 g) M.P. 91°-93° C. This trityl alcohol (3.2 g) and o-cresol (1.8 g) were dissolved in acetic acid (25 mL) and concentrated H2SO4) (0.5 mL) was added dropwise. A deep red color developed rapidly and the reaction mixture decolorized after 30 seconds. After five minutes, the mixture was poured into water, neutralized with NaOH solution, and extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered, evaporated in vacuo to give 9-(4-methoxyphenyl)-9-(3-methyl-4-hydroxyphenyl)fluorene (4.0 g) as an oil, which was used in the next step without further purification. Ethanethiol (3.7 g) was added dropwise to a stirred suspension of sodium hydride (2.3 g, 60% in mineral oil) in dry DMF (20mL). After the hydrogen bubbling had ceased, the above-mentioned oil was added and the mixture refluxed for 2 hours under nitrogen. The excess solvent was evaporated in vacuo and the residue extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered, evaporated in vacuo and the residue recrystallized from chloroform-hexane to give the title compound (2.5 g) as a solid. M.P. 186°-188° C.
Reaction SMILES: ClC1C(Cl)=CC=CC=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[Na+].[I-].[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]1CCCN(CCCCOC2C=C3C(CCC(=O)N3)=CC=2)CC1.CCN(C(C)C)C(C)C>CC#N>[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]1[CH2:9][CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: Clc1cccc(C2CCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1cccc(N2CCCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A mixture of intermediate 44 (43.7 mg, 0.17 mmol) and NaI (51.3 mg, 0.34 mmol) in CH3CN (3 mL) was heated to reflux for 30 min and then cooled to rt. To this mixture was added intermediate 2 (57.9 mg, 0.21 mmol), followed then by DIEA (0.066 mL, 0.38 mmol). The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by ISCO to give 6-(3-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)propoxy)-1H-indazole (compound 46) (43.6 mg, 61%). 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J=0.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.15-7.07 (m, 2H), 7.00 (dd, J=7.4, 2.3 Hz, 1H), 6.88 (s, 1H), 6.80 (dd, J=8.8, 2.1 Hz, 1H), 4.09 (t, J=6.1 Hz, 2H), 3.43-3.37 (m, 2H), 3.29 (t, J=6.1 Hz, 2H), 3.14-3.05 (m, 4H), 3.00-2.92 (m, 2H), 2.22-2.10 (m, 4H). HPLC: 99%, RT 4.201 min. MS (ESI) m/z 419.10 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14](OC)=O)[C:9]1=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:41]([OH:43])=O)[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:41](=[O:43])[C@H:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[NH:30][C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:29])[C@@H:10]([CH2:14][C:6]([O:5][CH3:1])=[O:19])[C:9]1=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 117.1 %

Procedure:
To a mixture of 28.8 g of (S)-3-methoxycarbonyl-2-oxopiperazine-1-acetic acid t butyl ester, 23.0 g of N-benzyloxycarbonyl-O-methyl-L-tyrosine and 202 ml of methylene chloride, 15.3 g of 1-(3-dimethylaminopropyl)-3-ehtylcarbodiimide was added. The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was disolved in ethyl acetate. The solution was washed with a 5% aqueous solution of potassium hydrogensulfate and a saturated sodium hydrogen carbonate. The organic layer was concentrated under reduced pressure to give 37.0 g of crude (S)-4-(N-benzyloxycarbonyl-O-methyl-L-tyrosyl)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid t butyl ester. This product was dissolved in 74.0 ml of methylene chloride, to which was added 74.0 ml of trifluoroacetic acid. The mixture was stirred for one hour at room temperature. The reaction solution was concentrated under reduced pressure. The residue was subjected to azeotropy with toluene several times to afford 39.12 g of the title compound as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.[CH:29](N(CC)C(C)C)(C)[CH3:30].ICC>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:28])[N:13]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:29][CH3:30])[CH2:24][CH2:23]2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCI
Product: CCN1CCC(CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.1 mg (0.12 mmol) of 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide are dissolved in 1 ml of 1,4-dioxane, and 25 μl (0.144 mmol) of N,N-diisopropylethylamine and 10 μl (0.12 mmol) of iodoethane are added. The mixture is stirred at room temperature overnight and, after concentration, chromatographed on silica gel (dichloromethane/methanol 97:3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].I[CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH2:33][CH2:34][CH2:35][CH3:36])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCSC1=NC(c2ccc(C#N)cc2)C(C(=O)OCC)=C(C)N1c1cccc(C(F)(F)F)c1

Procedure:
Ethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0.22 mmol), 1-iodobutane (45.0 mg, 0.25 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) are dissolved in 3 ml acetone and tired at room temperature overnight. The solvent is removed in vacuo and the product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[N:4]1([C:8]2[C:13]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH3:31])[C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)=O)=[C:12](Cl)[N:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5]1>O1CCOCC1>[N:4]1([C:8]2[N:9]=[CH:10][N:11]=[C:12]3[N:2]([CH3:1])[N:3]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:31])[C:20]=4[C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)[C:13]=23)[CH2:7][CH2:6][CH2:5]1
Reactant: Cn1ncc(C(=O)c2c(Cl)ncnc2N2CCC2)c1-c1ccc(C(F)(F)F)cn1
Reactant: CNN
Solvent: C1COCCO1
Product: Cn1ncc(-c2nn(C)c3ncnc(N4CCC4)c23)c1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methylhydrazine (98%, 0.254 mL, 4.73 mmol) was added to a solution of [4-(azetidin-1-yl)-6-chloropyrimidin-5-yl]{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanone (C16) (200 mg, 0.473 mmol) in 1,4-dioxane (4 mL), and the reaction mixture was allowed to stir for 18 hours at room temperature. After removal of solvent in vacuo, the residue was chromatographed on silica gel to provide the product as a solid. Yield: 120 mg, 0.290 mmol, 61%. LCMS m/z 415.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.25-2.34 (m, 2H), 3.79-4.04 (br m, 4H), 3.94 (s, 3H), 3.98 (s, 3H), 7.80 (s, 1H), 7.85 (d, J=8.2 Hz, 1H), 8.12-8.16 (m, 1H), 8.17 (s, 1H), 8.77-8.79 (m, 1H).
Reaction SMILES: O=[C:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]2)[CH:3]([CH3:8])[CH2:4][C:5]([OH:7])=O.[NH:21]([CH2:23][CH2:24][OH:25])[NH2:22]>C(O)C>[OH:25][CH2:24][CH2:23][N:21]1[C:5](=[O:7])[CH2:4][CH:3]([CH3:8])[C:2]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)=[N:22]1
Reactant: NNCCO
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)CCC(=O)N2C
Solvent: CCO
Product: CC1CC(=O)N(CCO)N=C1c1ccc2c(c1)CCC(=O)N2C
Yield: 80.2 %

Procedure:
A solution of 2.72 g of 4-oxo-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-methylbutanoic acid and 1.5 g of 2-hydrazinoethanol in 30 ml of ethanol was heated under reflux on a water bath for 2 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The precipitated crystals were filtered off and recrystallized from isopropanol to give 2.5 g of 6-[2-(2-hydroxyethyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-1-methyl-1,2,3,4-tetrahydroquinolin-2-one as colorless crystals, melting at 171°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)nc1
Yield: 74.5 %

Procedure:
After dissolving 6-bromonicotinic acid (65.7 g, 0.325 mol) in tetrahydrofuran (1600 ml), triethylamine (54 ml, 0.39 mol) and ethyl chloroformate (32.6 ml, 0.341 mol) were added while stirring on ice. The mixture was stirred for 20 minutes while cooling on ice, and the white crystals which precipitated upon filtration were removed and washed with tetrahydrofuran. The filtrate was stirred while cooling on ice, and an aqueous solution (211 ml) of sodium borohydride (18.4 g, 0.488 mol) was gradually added dropwise over a period of 30 minutes. After continued stirring for 1 hour and 20 minutes while cooling on ice, 800 ml of water was added and extraction was performed with ethyl acetate (600 ml×2), and then after washing the combined organic layers with brine (300 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield the title compound (45.5 g, 74.5%). This was used without further purification for the following reaction.
Reaction SMILES: [C:1]([O:8][CH:9]([CH2:11][C:12]1[C:13]2[C:18]([CH:19]=[C:20]3[C:25]=1[CH:24]=[CH:23][CH:22]=[CH:21]3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].Br[C:27]1[C:28]2[C:33]([CH:34]=[C:35]3[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]3)=[CH:32][CH:31]=[CH:30][CH:29]=2.[CH:41]1[C:54]2[C:45](=[CH:46][C:47]3[C:52]([C:53]=2[CH2:55]O)=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:44]=[CH:43][CH:42]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:8][CH:9]([CH2:10][C:27]1[C:40]2[C:35]([CH:34]=[C:33]3[C:28]=1[CH:29]=[CH:30][CH:31]=[CH:32]3)=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][C:12]1[C:25]2[C:20]([CH:19]=[C:18]3[C:13]=1[CH:14]=[CH:15][CH:16]=[CH:17]3)=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:7])[CH2:2][CH2:3][C:4]([O:6][CH2:55][C:53]1[C:54]2[C:45]([CH:46]=[C:47]3[C:52]=1[CH:51]=[CH:50][CH:49]=[CH:48]3)=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:5]
Reactant: CC(Cc1c2ccccc2cc2ccccc12)OC(=O)CCC(=O)O
Reactant: OCc1c2ccccc2cc2ccccc12
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCC(=O)OC(Cc1c2ccccc2cc2ccccc12)Cc1c2ccccc2cc2ccccc12)OCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of 1,3-di-(9-anthryl2-propyl hydrogen succinate (4) (103.3 mgr, 0.20 mmoles) prepared from 9-bromoanthracene (A. Castellan, L. Kessab, S. Grelier, A. Nourmamode, M. Cotrait, P. Marsau, J. Chem. Soc. Perkin Trans. 2, 1993, 953-961) (scheme 1), and 9-anthracene methanol (60.7 mgr, 0.29 mmoles), in dry dichloromethane (0.2 ml) a catalytic amount of 4-dimethylaminopyridine (4-DMAP) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (42.48 mgr, 0.222 mmoles) was added, at ice bath temperature. The reaction mixture was stirred overnight under argon, at room temperature and then it was partitioned between water and ethyl acetate. The aqueous phase was washed with ethyl acetate twice and the combined organic extracts were washed with saturated ammonium chloride, water, brine, dried over sodium sulfate and concentrated in vacuo. The crude mixture was subjected to flash chromatography to afford 99.4 mgr (70%) of 1,3-di-(9-anthryl)-2-propyl 9-anthrylmethyl succinate which was further purified by recrystallization from dichloromethane (yellow crystals). 1H NMR (250 MHz, CDCl3): δ 8.35 (5H, m), 8.00 (10H, d), 7.50-7.10 (12H, m), 6.10 (2H, s), 5.70 (1H, m), 4.10 (2H, dd), 3.65 (2H, dd), 2.10 (4H, t); 13C NMR (62.5 MHz, CDCl3): δ 131.54, 131.15, 130.38, 129.62, 128.85, 126.92, 125.38, 124.62, 123.85, 63.85, 31.54, 30.38, 29.23, 28.46 ppm; FTIR 3050.0, 2920.0, 1723.9, 1158.7, 891.3, 731.0 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]#[CH:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[N:41]([C@@H:44]([CH2:71][C:72]1[CH:77]=[CH:76][C:75]([O:78][CH2:79][CH2:80][O:81][S:82]([C:85]2[CH:91]=[CH:90][C:88]([CH3:89])=[CH:87][CH:86]=2)(=[O:84])=[O:83])=[CH:74][CH:73]=1)[C:45]([N:47]([C@@H:55]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:46])=[N+:42]=[N-:43].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu]I>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[N:43]=[N:42][N:41]([C@@H:44]([CH2:71][C:72]5[CH:73]=[CH:74][C:75]([O:78][CH2:79][CH2:80][O:81][S:82]([C:85]6[CH:91]=[CH:90][C:88]([CH3:89])=[CH:87][CH:86]=6)(=[O:84])=[O:83])=[CH:76][CH:77]=5)[C:45]([N:47]([C@@H:55]([CH2:60][C:61]5[CH:62]=[CH:63][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:65][CH:66]=5)[C:56]([O:58][CH3:59])=[O:57])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:46])[CH:26]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:38][CH:37]=1
Reactant: C#CCOc1ccc2nc(S(=O)(=O)NC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)sc2c1
Reactant: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1)N=[N+]=[N-]
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)C(=O)[C@H](Cc1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1)n1cc(COc2ccc3nc(S(=O)(=O)NC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)sc3c2)nn1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a stirring solution of N-(bis(4-methoxyphenyl)(phenyl)methyl)-6-(prop-2-ynyloxy)benzo[d]thiazole-2-sulfonamide (83 mg, 0.145 mmol) and the Boc-protected amide 151 (107 mg, 0.145 mmol) in THF (0.7 mL) was added copper(I) iodide (3 mg, 0.0145 mmol) then diisopropylethylamine (28 μL, 0.16 mmol). The mixture was allowed to stir for 2 h at 23° C. then concentrated in vacuo and the crude residue purified by flash chromatgraphy on silica gel using hexanes/ethyl actetate on a Biotage purification system yielding the desired product as a yellow, crystalline solid (145 mg, 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][O:12][CH:11]3[CH:14]([O:17][CH3:18])[CH2:15][O:16][CH:10]23)[C:5]([Cl:19])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl.[CH3:30][N:31]1[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]1>CCCCO>[Cl:19][C:5]1[C:6]([NH:8][CH:9]2[CH2:13][O:12][CH:11]3[CH:14]([O:17][CH3:18])[CH2:15][O:16][CH:10]23)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: COC1COC2C(Nc3nc(Cl)ncc3Cl)COC12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC1COC2C(Nc3nc(Nc4cnn(C)c4)ncc3Cl)COC12
Yield: 42.7 %

Procedure:
A solution of 2,5-dichloro-N-(6-methoxyhexahydrofuro[3,2-b]furan-3-yl)pyrimidin-4-amine (430 mg, 1.4046 mmol), DIPEA (546.7 mg, 4.23 mmol) and 1-methylpyrazol-4-amine hydrochloride (283.3 mg, 2.12 mmol) in n-BuOH (10 mL) was stirred in a sealed tube at 150° C. for 23 h. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the crude product as a white solid. The crude product was recrystallized from acetone to give the title compound as a white solid (220 mg, 42.6%).