Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:14]3[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(C2(O)c3ccccc3C=Cc3ccc(I)cc32)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(=C2c3ccccc3C=Cc3ccc(I)cc32)CC1

Procedure:
A solution of 3.23 g. of 1-methyl-4-(3-iodo-5-hydroxy-5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 30 ml. of trifluoroacetic acid and 10 ml. of trifluoroacetic anhydride is refluxed for 6 hours. The solution is concentrated on a rotary evaporator and the residue is made basic with 5% sodium hydroxide solution. The oil that precipitates is extracted into ether, and this ether phase is washed with water, dried over magnesium sulfate, filtered, and the ether removed on a rotary evaporator. The residue is triturated with acetonitrile, collected and dried to give 2.36 g. of material. This material is recrystallized from ethyl acetate to give pure (±)-1-methyl-4-(3-iodo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 166°-170°.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:10]([N:4]1[C:3](=[O:9])[C:2]([I:1])=[CH:7][NH:6][C:5]1=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: O
Product: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-iodouracil (commercially available from Aldrich, 2 g, 8.4 mmol) in dry pyridine (20 mL) was added dropwise to a solution of benzoyl chloride (3.5 g, 25.3 mmol) in pyridine (10 mL). The mixture was stirred at room temperature for 3 hours. Water (70 mL) was added and the product extracted with ethyl acetate. The organic phase was washed with a saturated solution of NH4Cl and then with 2% HClaq(40 mL×4 times) The solvent was removed under vacuum and the residue was triturated with i-Pr2O to give the title compound as white solid (2.6 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:16]C1C=C(C=CC=1)CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[CH3:16][C:7]1[CH:2]=[C:3]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Reactant: Cc1cccc(CBr)c1
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1cccc(C)c1
Yield: 72 %

Procedure:
The title compound was prepared as described for B4 using 3-methylbenzyl bromide (1.250 g, 6.75 mmol), magnesium (0.181 g, 7.43 mmol) and diethyl oxalate (1.974 g, 13.51 mmol). The resulting compound was isolated in the form of colorless oil in 72% yield and use instantly in next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[CH:12]=[CH2:13].[BH4-].[Na+]>CC(C)=O.CO>[CH2:13]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: c1cnc2ccncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: C=CCN1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-naphthyridine (6.5 g, 0.05 mol) and allyl bromide (9.1 g, 0.075 mol) in acetone (50 ml) was refluxed for 8 hours. The precipitated quatenary salt was separated by filtration, dissolved in technical grade methanol (300 ml) and sodium borohydride (18.9 g, 0.5 mol) was added portionwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with benzene. The benzene layer was dried over anhydrous potassium carbonate and evaporated in vacuo. The residue was purified by alumina column chromatography (eluted successively with n-hexane and benzene-chloroform (3:1)) and distilled, bp 98° C./1.0 mmHg, to afford the Compound No. 12 (5.70 g, 65.5%) as a colorless oil.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[CH3:11][NH:12][NH2:13]>C(O)C>[NH2:8][C:7]1[N:12]([CH3:11])[N:13]=[C:4]([CH3:5])[C:6]=1[C:9]#[N:10]
Reactant: CNN
Reactant: CCOC(C)=C(C#N)C#N
Solvent: CCO
Product: Cc1nn(C)c(N)c1C#N
Temperature: 25 °C
Yield: 68 %

Procedure:
2-(1-Ethoxy-ethylidene)-malononitrile 1a (10 g, 73.45 mmol) was added portionwise to a mixture of N-methylhydrazine (1 equiv., 3.88 ml) in ethanol (50 ml) and the reaction mixture was refluxed for 1 hour, cooled to room temperature, precipitate filtered, washed with ethanol and dried to give 5-amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile 2a as white crystalline solid (9.85 g, 68%).
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][N:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH2:5][CH2:6][CH2:7][NH2:8].[CH2:16]1[O:18][CH:17]1[CH2:19][OH:20]>CO>[OH:1][CH:2]([CH2:14][OH:15])[CH2:3][N:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH2:5][CH2:6][CH2:7][NH:8][CH2:16][CH:17]([OH:18])[CH2:19][OH:20]
Reactant: NCCCN(CC(O)CO)CC(O)CO
Reactant: OCC1CO1
Solvent: CO
Product: OCC(O)CNCCCN(CC(O)CO)CC(O)CO

Procedure:
N,N-di-(2,3-dihydroxypropyl)trimethylenediamine (11.1 g., 0.05 mole) was dissolved in 125 ml. of methanol and heated under reflux with agitation. Glycidol (3.7 g., 0.05 mole) was added dropwise over a period of 1.5 hour and the solution mixed an additional hour at 60° C.-80° C. The methyl alcohol and other volatiles were removed by stripping under reduced pressure to leave the product suitable for use in the next steps.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[C:15]1(=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[CH2:16]1>CN(C)C1C=CN=CC=1.ClCCCl>[C:8]([CH:16]1[C:15](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:24])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)C1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Yield: 63 %

Procedure:
A mixture of 4-dimethylaminopyridine (664 mg, 5.44 mmol), triethylamine (7.6 ml 54.56 mmol), acetic anhydride (6.2 ml, 65.48 mmol in dry 1,2-dichloroethane (60,ml) was stirred at −20° C. and a solution of 1,3-indanedione (7.96 g, 54.56 mmol) in 1,2-dichloroethane was added dropwise in 1.5 h. The reaction mixture was stirred for 30 min, then washed with 10% hydrochloric acid (80 ml) and twice with water (80 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallized from methyl-tert-butylether (50 ml) to give 2-acetyl-1,3-indanedione 38(6.5 g 63%). Rf 0.27 (hexane-ethylacetate-acetic acid 20-5-0.5) MS C11H8O3 m/z (%) 189 [M+H]+ (100), 166 (72), 104 (20).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[S:18])[NH2:17])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.Br[CH2:24][C:25]([C:27]1[CH2:31][C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][N:28]=1)=O>C(O)C.O>[C:32]1([C@@H:30]2[O:29][N:28]=[C:27]([C:25]3[N:17]=[C:16]([CH:13]4[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][N:6]5[C:2]([CH3:1])=[CH:3][C:4]([C:19]([F:22])([F:20])[F:21])=[N:5]5)[CH2:11][CH2:12]4)[S:18][CH:24]=3)[CH2:31]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)C1=NO[C@@H](c2ccccc2)C1
Solvent: O
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NO[C@@H](c4ccccc4)C3)cs2)CC1
Temperature: 50 °C

Procedure:
A mixture of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidine-carbothioamide (i.e. the product of Example 8, Step C) (1.7 g, 5.0 mmol) and 2-bromo-1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]ethanone (i.e. the product of Example 12, Step E) (1.35 g, 5 mmol) in ethanol (15 mL) was heated at 50° C. for 30 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to give the title product as a pale-yellow gum. High performance liquid chromatography (HPLC) analysis showed that the title product was about 95% pure and contained the (R)-enantiomer in about 98% enantiomeric excess.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:29]
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:27])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:27]([S:29]([CH3:28])(=[O:31])=[O:30])[S:29]([CH3:28])(=[O:31])=[O:30])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nc3ccc(N)cc3nc2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-bis(4-methoxyphenyl)quinoxalin-6-amine (123.2 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (20 mL) was added methanesulfonyl chloride (47.2 mg, 0.41 mmol, 1.20 equiv) and triethylamine (174.3 mg, 1.73 mmol, 5.00 equiv). The resulting solution was stirred for 1.5 h at room temperature. The resulting mixture was concentrated in vacuo, resulting in 179.55 mg (81%) of N-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)-N-(methylsulfonyl)methanesulfonamide as a brown solid.
Reaction SMILES: [CH2:1]([NH:8]CCC1C2C(=CC=C(F)C=2OC)N(C)C=1)C1C=CC=CC=1.[F:24][C:25]1[CH:26]=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:28]([O:38][CH3:39])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][CH2:36]O>>[F:24][C:25]1[CH:26]=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:28]([O:38][CH3:39])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][CH2:36][NH:8][CH3:1]
Reactant: COc1c(-c2ccccc2)cc(F)c2c1c(CCO)cn2C
Reactant: COc1c(F)ccc2c1c(CCNCc1ccccc1)cn2C
Product: CNCCc1cn(C)c2c(F)cc(-c3ccccc3)c(OC)c12
Yield: 47 %

Procedure:
Following the procedure (step 6, scheme 17) used to prepare compound 17-7, compound 22-4 was used as starting material, giving compound 22-5 in 47% yield as a colorless oil, which was converted to the hydrochloride salt. 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 8.63 (br, 2H), 7.57-7.60 (m, 2H), 7.45 (t, J=7.4 Hz, 2H), 7.30-7.36 (m, 1H), 7.23 (s, 1H), 6.93 (d, J=12.9 Hz, 1H), 3.90 (d, J=1.9 Hz, 3H), 3.36 (s, 3H), 3.16-3.21 (m, 2H), 3.06-3.11 (m, 2H), 2.59 (s, 3H). LRMS: calc 312.2 found 313.1 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O=[C:25]([CH2:29][CH2:30][CH3:31])[CH2:26][C:27]#[N:28].CS(O)(=O)=O.O>C1(C)C=CC=CC=1>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:25]([CH2:29][CH2:30][CH3:31])[C:26]([C:27]#[N:28])=[C:16]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: CCCC(=O)CC#N
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1nc2ccc(O)cc2c(-c2ccccc2)c1C#N
Yield: 55.7 %

Procedure:
A solution of (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-phenyl)(phenyl)methanone (2.0 g, 6.1 mmol), 3-oxohexanenitrile (0.81 g, 7.3 mmol) and methanesulfonic acid (0.59 g, 6.1 mmol) in toluene (50 ml) was stirred at 110° C. for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from disopropyl ether to give 6-hydroxy-4-phenyl-2-propylquinoline-3-carbonitrile (0.98 g, yield 56%) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(Oc2ccc([N+](=O)[O-])cc2C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.050 moles) of 2-chloro-5-nitrobenzonitrile, 6.39 g (0.0515 moles) of 3-methoxyphenol, 7.10 g (0.0515 moles) of anhydrous potassium carbonate (K2CO3) and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from approximately 200 ml of absolute ethanol to give 7.15 g (53% yield) of purified 2-(3-methoxyphenoxy)-5-nitrobenzonitrile, mp 102°-103.5° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C.[CH2:32]=[C:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:37]([CH:35]2[CH2:36][C:33](=[CH2:32])[CH2:34]2)=[O:38])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: NCc1nccnc1Cl
Reactant: C=C1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol, 1.4 eq.), 4-dimethylamino pyridine (DMAP) (0.141 g, 1.15 mmol, 0.25 eq.), and DIEA (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) were dissolved in anhydrous CH2Cl2 (25 mL). To this solution, a solution of 3-methylenecyclobutanecarboxylic acid (0.622 g, 5.54 mmol, 1.2 eq.) in anhydrous CH2Cl2 (25 mL) was added under N2 and the reaction was allowed to stir overnight at rt. Reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with water (2×), NaHCO3 (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with 10% hexane in ethyl acetate, affording the title compound as a pale yellow solid. Additionally, the title compound could be prepared by the following route: 1,1′-Carbonyldiimidazole (CDI) (0.824 g, 5.08 mmol, 1.1 eq.) and 3-methylenecyclobutanecarboxylic acid (0.570 g, 5.08 mmol, 1.1 eq.) were dissolved in anhydrous THF (12 mL) and allowed to stir at 60° C. for 2 h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol) and DIEA (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) in anhydrous CH2Cl2 (13 mL) was added to the acid mixture and the reaction was allowed to stir at 60° C., under N2, overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with NaHCO3 (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with 10% hexane in ethyl acetate, affording the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.86-2.96 (m, 2H), 3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78 (s, —NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, 1H); MS (ES+): m/z 238.19 (90) [MH+]; HPLC: tR=2.67 min (OpenLynx, polar 7 min).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12]2[N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:15]([CH3:24])=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:13]=2)[CH:8]=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:12]2[N:16]([CH2:17][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:15]([CH3:24])=[C:14]([S:25](=[O:27])(=[O:26])[NH2:28])[CH:13]=2)[CH:6]=1)[O:11][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCBr
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCOc1cc(-c2cc(S(N)(=O)=O)c(C)n2CC2CCCCC2)cc(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of compound 14 (202 mg, 0.5 mmol) in DMF (20 mL) were added Cs2CO3 (325 mg, 1 mmol) and methyl 4-bromobutanoate (99 mg, 0.55 mmol). The reaction mixture was stirred for 4 h at 40° C., then water (30 mL) was added and the reaction mixture was extracted with EA (150 mL). The organic layer was washed with brine and dried over Na2SO4, concentrated and purified by CC (hexane/EA=3/1) to give compound 15 (176 mg, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
A mixture of 1-(3-bromo-phenyl)-ethanone (4.9 g, 24 mmol), 4-trifluoromethyl phenyl boronic acid (4.6 g, 24 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 g, 1.2 mmol), potassium phosphate (10 g, 49 mmol), 1,2-dimethoxyethane (50 mL) and water (10 mL) was heated to 80° C. under a blanket of nitrogen in a sealed tube. After 5 h, the mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified directly by FCC to afford a clear oil (5.6 g, 87%). MS (ESI): mass calcd. for C15H11F3O, 264.0; m/z found, 265.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.21 (t, J=1.6, 1H), 8.04-7.98 (m, 1H), 7.85-7.78 (m, 1H), 7.76-7.69 (m, 4H), 7.60 (t, J=7.7, 1H), 2.68 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[C:11]#[N:12].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.ClCCl>[C:20]([NH:12][CH2:11][C:10]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=1[NH2:8])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1CNC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Triethylamine (116 ml, 0.835 mol) and DMAP (2.0 g, 0.016 mol) are added to 2-amino-5-nitrobenzonitrile (68 g, 0.33 mol) in dichloromethane (1 litre). The mixture is cooled to +5° C., and benzoyl chloride (38.8 ml, 0.33 mol) in dichloromethane (50 ml) is added. The resulting mixture is stirred for 2 hours and then concentrated. The residue is taken up in 10/1 water/ethanol (550 ml) and the product is filtered off and recrystallized from isopropyl ether. Yield: 88.5 g (97%); IR (KBr): 3375, 3213, 1638, 1547, 1319 cm−1; 1H-NMR (d6-DMSO) 8.15 (m, 1H); 7.85 (m, 4H); 7.51 (m, 4H); 6.68 (m, 3H); 4.30 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2.C([BH3-])#N.[Na+].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2
Reactant: CN(C)C=Cc1ccc([N+](=O)[O-])c2[nH]ncc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C)CCc1ccc([N+](=O)[O-])c2[nH]ncc12
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
16.2 g of N,N-dimethyl-N-[2-(7-nitro-1H-indazol-4-yl)ethenyl]amine is dissolved in 200 ml of acetic acid and combined under ice cooling in incremental portions with 6.3 g of sodium cyanoborohydride within 30 minutes. After another 30 minutes, the mixture is combined with ice and ethyl acetate, adjusted to 8-9 with concentrated sodium hydroxide solution, and extracted with ethyl acetate. The solution is dried, concentrated, and the residue recrystallized from ethyl acetate/diisopropyl ether, thus obtaining 13.8 g of N,N-dimethyl-N-[2-(7-nitro-1H-indazol-4-yl)ethyl]amine, mp 145°-146° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:38])[CH2:17][CH2:18][N:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[C:31]([O:33][CH3:34])[C:30]([OH:35])=[C:29]([O:36][CH3:37])[CH:28]=4)=[N:25][CH:26]=3)[CH3:20])=[CH:12][N:11]=2)=[CH:4][C:3]=1[O:39][CH3:40].[CH3:41][S:42]([OH:45])(=[O:44])=[O:43]>N1C=CC=CC=1.CO>[CH3:41][S:42]([OH:45])(=[O:44])=[O:43].[CH3:41][S:42]([OH:45])(=[O:44])=[O:43].[C:2]([O:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH3:38])[CH2:17][CH2:18][N:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:28]=[C:29]([O:36][CH3:37])[C:30]([O:35][C:31](=[O:33])[CH2:30][CH2:29][CH3:28])=[C:31]([O:33][CH3:34])[CH:32]=4)=[N:25][CH:26]=3)[CH3:20])=[CH:12][N:11]=2)=[CH:4][C:3]=1[O:39][CH3:40])(=[O:1])[CH2:3][CH2:4][CH3:5]
Reactant: COc1cc(-c2ccc(N(C)CCN(C)c3ccc(-c4cc(OC)c(O)c(OC)c4)nc3)cn2)cc(OC)c1O
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Solvent: CO
Product: CCCC(=O)Oc1c(OC)cc(-c2ccc(N(C)CCN(C)c3ccc(-c4cc(OC)c(OC(=O)CCC)c(OC)c4)nc3)cn2)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 118 %

Procedure:
To a solution of N,N′-bis[2-(4-hydroxy-3,5-dimethoxyphenyl)-5-pyridyl]-N,N′-dimethylethylenediamine (74.0 mg, 0.135 mmol) synthesized as described in Example 14 in pyridine(1.5 mL)wasaddedbutyricanhydride(101.mg,0.640 mmol). After stirring at room temperature for 12 hours, the reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium carbonate, and concentrated under reduced pressure. To a solution of the residue in methanol (2.0 mL) was added a 1.0 M aqueous methanesulfonic acid (0.27 mL, 0.27 mmol), and the reaction mixture was concentrated under reduced pressure. Ethanol (5.0 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was recrystallized from chloroform-diethyl ether to afford the title compound as a yellow crystalline powder (melting point: 196.0-200.0° C.)(70.0 mg, yield: 59%).