Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[S:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:7]1[S:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1csc(S(N)(=O)=O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1cc(S(N)(=O)=O)sc1Br
Temperature: 0 °C
Reaction time: 7 h
Yield: 82.1 %

Procedure:
To a solution of 4-methoxythiophene-2-sulfonamide (240 mg, 1.24 mmol) in CH2Cl2 (40 mL) is added N-bromosuccinimide (287 mg, 1.61 mmol). The reaction mixture is stirred at 0° C. for 7 hr. After 7 hr, the reaction mixture is diluted with CH2Cl2 (150 mL). The organic layer is washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with Hex:EtOAc (2:1) to afford the title compound (277 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[S:17][C:11]=2[N:10]=[C:9]1[CH3:22].O.[NH3:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([S:18](=[O:20])(=[O:19])[NH2:24])[S:17][C:11]=2[N:10]=[C:9]1[CH3:22]
Reactant: Cc1nc2sc(S(=O)(=O)Cl)cc2c(=O)n1-c1ccccc1Cl
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2sc(S(N)(=O)=O)cc2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In 200 ml of tetrahydrofuran was suspended 23 g of 3,4-dihydro-3-(2-chlorophenyl)-6-chlorosulfonyl-2-methyl-4-oxothieno[2,3-d]pyrimidine, and this suspension was poured onto 200 ml of ammonia water at one time. The mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated, and water was added to the residue. The crystals were collected by suction-filtration to afford 15.8 g of the title compound, m.p. 251° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[F:27][C:25]([F:26])([F:28])[C:24]([NH:23][C:22]1[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:29]
Reactant: O=C(OCc1ccccc1)N1CCN(c2ncccc2NC(=O)C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1cccnc1N1CCNCC1)C(F)(F)F
Reaction time: 20 h

Procedure:
1-[Benzyloxycarbonyl]-4-[3-(2,2,2-trifluoroacetamido)-2-pyridinyl]piperazine (PREPARATION 34), is dissolved in 70 ml of ethanol and 0.25 g of 10% palladium on carbon is added. The reaction is hydrogenated at 40 psi for 20 hr. Then it is filtered through a pad of celite and concentrated in vacuo to afford the title compound which is used without further purification, NMR (300 MHz, CDCl3) 8.51, 8.21, 7.19, and 3.45-3.47 δ.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][S:16]2(=[O:21])=[O:20])[CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:30])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:24][C:23]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)([CH3:30])[CH3:22])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][S:16]2(=[O:21])=[O:20])[CH2:2][CH2:3]1
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(N2CCCS2(=O)=O)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(1,1-dioxido-isothiazolidin-2-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=437.0 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:68])[C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[C:64]([F:67])([F:66])[F:65])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[F:63][C:61]1[CH:60]=[CH:59][C:58]([C:64]([F:66])([F:65])[F:67])=[C:57]([CH:62]=1)[C:56]([N:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1)=[O:68]
Reactant: O=C(O)c1cn(-c2ccccc2)nn1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cn(-c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 83.1 %

Procedure:
DIPEA (140 mg, 0.19 mL, 1.08 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid (40 mg, 0.21 mmol) in DMF (5 mL). HOBT (32 mg, 0.23 mmol) and EDCI (102 mg, 0.53 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (90 mg, 0.24 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 88 mg (82.2% yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 100%. 1H NMR (DMSO-d6): δ 9.4 (s, 1H), 8.76 (t, 1H), 8.04 (m, 3H), 7.7-7.46 (m, 5H), 4.3 (d, 2H), 3.8-3.4 (m, 6H), 3.28 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13]
Reactant: COC(=O)c1ccc(Cl)cc1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)cc1N(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(O)cc1

Procedure:
A solution of the title D compound, 2-[(4-benzyloxy-benzenesulfonyl)-(t-butoxycarbonyl)-amino]-4-chloro-benzoic acid methyl ester (2.45 g, 4.61 mmol) in 30 mL of EtOAc containing 1.2 g of 10% palladium on carbon is shaken under 50 psi of hydrogen at RT overnight. The mixture is then filtered and concentrated to give 2-[(4-hydroxybenzene-sulfonyl)-(t-butoxycarbonyl)amino]4-chloro-benzoic acid methyl ester as a white foam.
Reaction SMILES: [OH-].[Na+:2].[F:3][C:4]([F:21])([F:20])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([OH:19])(=[O:18])=[O:17]>C(O)C>[F:20][C:4]([F:3])([F:21])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([O-:19])(=[O:18])=[O:17].[Na+:2]
Reactant: O=S(=O)(O)CCCCCCCCCCOC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)([O-])CCCCCCCCCCOC(F)(F)F

Procedure:
1.15 g (28.8 mmol; 1.3 eq) of NaOH are dissolved in 60 ml of ethanol and added at RT to the sulfonic acid from Example 5c (6.8 g; 22.2 mmol; 1 eq). After refluxing for 1 h, a colourless solid is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:23]O>>[OH:14][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([O:13][CH3:23])=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: CO
Reactant: COC1=CC(=O)c2ccccc2C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: COc1cc(OC)c2ccccc2c1O
Reaction time: 1 h

Procedure:
A solution of 18.9 g of 2-methoxynaphthoquinone in methanol was added slowly to a solution of 34.8 g of sodium hydrosulfite in methanol and the mixture stirred for 1 hour. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and evaporated to a purple solid. The solid was dissolved in 200 ml of methanol previously saturated with anhydrous hydrochloric acid and stirred for 3 minutes at 60° C. The mixture was then diluted with 200 ml of ice water and the precipitate filtered off, dried under vacuum and recrystallized from ether/pentane to give 13.25 g of 1-hydroxy-2,4-dimethoxynaphthalene, m.p. 87°-88° C.
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[O:1]=[C:2]([O-:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH3+:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH3+:24]
Reactant: NCCCCCCCCN
Reactant: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)[O-]
Product: [NH3+]CCCCCCCC[NH3+]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Aqueous D-glucaric acid (1, ˜1 M, 4.51 mL) and aqueous octamethylenediamine (1 M, 5.94 mL) were mixed in a round bottom flask, and stirred at room temperature for 10 min. The reaction mixture was then stirred at 60° C. for 26 h and concentrated to less than 25% of the total volume. Methanol (6˜8 mL) was added drop-wise to the concentrated solution and the reaction mixture was stirred for 12 h. The top methanol phase was removed and the light amber syrup was washed with methanol (2×5 mL), and then dried under vacuum at room temperature for 24 h to give octamethylenediammonium D-glucarate (5a)/1 and 6-[N-(8-ammoniumooctyl)]-D-glucaramates (5b and 5c) (1.54 g, 4.35 mmol, 96.43%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]#[N:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[F:14][C:11]1[NH:10][CH:9]=[C:8]([C:12]#[N:13])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: N#Cc1c[nH]c(F)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 35.6 %

Procedure:
To a solution of 9.50 g (56.5 mmol) of 4-phenyl-1H-pyrrole-3-carbonitrile (CAS 40167-37-1) in 300 ml of acetonitrile are added portionwise 24.0 g (67.8 mmol) of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectFluor—CAS 140681-55-6), with a certain amount of exothermicity being observed. The mixture is stirred for 18 hours at 60° C. After cooling, the reaction medium is concentrated under reduced pressure and the residue is then taken up in 500 ml of ethyl acetate. The solution is washed twice with 250 ml of water and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown oil, which is chromatographed on a column of silica gel, eluting with a mixture of 15% ethyl acetate in cyclohexane, to give 3.75 g of 5-fluoro-4-phenyl-1H-pyrrole-3-carbonitrile in the form of a red oil after drying, which product is used as obtained for the rest of the synthesis.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.[C:26](Cl)(=[O:34])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[C:26](=[O:34])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:5]=4[C:6]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: CCCCCCOC(=O)Oc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl hexyl carbonate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedures described for Example 138, but using hexyl carbonochloridate. LRMS [M+H]=458.2.
Reaction SMILES: [C:1]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:18].C(O)(=O)C>>[Br:18][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:16])=[O:17]
Reactant: O=C1CCCCCCCCCCCCCCO1
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCBr
Reaction time: 16 h

Procedure:
15-Pentadecanolide of 14.3 g (59.5 mmol), and 32% hydrogen bromide/acetic acid solution of 24.8 g (98.0 mmol, 1.6 eq) were added to 100 mL of autoclave protected with Teflon (registered trade name). After purging with nitrogen and sealing, the autoclave was placed in an oil bath at 60° C. and stirring was carried out for 16 hours. For the stirring, a magnetic stirrer was used. After cooling, 14 mL of water was added, and by using 200 mL of hot hexane the mixture was transferred to a separatory funnel. After washing with ion exchange water, it was dried over the magnesium sulfate. After filtration, 17.4 g of the target compound was obtained by crystallization using n-hexane (yield 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1>Cl>[NH2:8][C:5]1[C:4]([CH:15]=[O:16])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: CC(C)(C)C(=O)Nc1ncc(Cl)cc1C=O
Agent: Cl
Product: Nc1ncc(Cl)cc1C=O
Temperature: 25 °C
Yield: 121.9 %

Procedure:
The product of Step 2 (2.7 g, 11 mmol) and 3 N HCl (50 mL) were heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and was concentrated in vacuo yielding a light yellow solid (2.1 g). The solid was partitioned between ethyl acetate and 2.5 N NaOH solution. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo providing a solid (1.7 g). The solid was recrystallized from ethyl acetate to give the desired substituted pyridine as yellow needles (1.2 g, 68%): mp 176.1–177.3° C. 1H NMR (CDCl3/300 MHz) 9.80 (s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 6.75 (br s, 2H). Anal. Calc'd for C6H5N2OCl: C, 46.03; H, 3.22; N, 17.89 Found: C, 45.90; H, 3.24; N, 17.80.
Reaction SMILES: CN(C)CC[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]([CH:22]([CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:9].[CH3:44][NH:45][CH3:46].[CH2:47](O)C>>[CH3:44][N:45]([CH3:47])[CH2:46][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]([CH:22]([CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:9]
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCN(C)C
Reactant: CNC
Reactant: CCO
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCN(C)C

Procedure:
Using an analogous procedure to that described for the synthesis of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-(dimethylamino)hexanoate 11, (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 5-(dimethylamino)pentanoate 13 was obtained as a pale yellow oil (1.9 g, 62%) from 5.6 M dimethylamine in ethanol (20 mL). 1H NMR (400 MHz, CDCl3) δ 5.45-5.28 (m, 6H), 4.95-4.90 (m, 1H), 2.34-2.23 (m, 4H), 2.23-2.20 (s, 6H), 2.06-1.92 (m, 12H), 1.70-1.58 (m, 5H), 1.58-1.44 (m, 5H), 1.44-1.15 (m, 25H), 0.92-0.87 (m, 9H). Rf 0.4 (10% MeOH—CH2Cl2).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[O:28]=[C:27]1[CH:26]([N:25]2[C:21](=[O:23])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:15]2=[O:17])[CH2:32][CH2:31][C:30](=[O:33])[NH:29]1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(Nc2ccc3ccccc3c2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(Nc4ccc5ccccc5c4)c3C2=O)C(=O)N1
Yield: 92 %

Procedure:
A mixture of 3-(naphthalen-2-ylamino)phthalic acid (0.62 g, 1.8 mmol) and rac-α-aminoglutarimide hydrochloride (0.33 g, 2.0 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 95:5 methylene chloride-methanol, eluting 0.74 g of the product, in 92% yield: mp 235-237° C.; 1H NMR (DMSO-d6) δ 2.06-2.11 (m, 1H), 2.54-2.64 (m, 2H), 2.85-3.00 (m, 1H), 3.77 (s, 3H), 5.15 (dd, J=12.7 Hz, J=5.3 Hz, 1H), 7.29 (d, J=6.3 Hz, 1H), 7.39-7.52 (m, 3H), 7.57-7.69 (m, 2H), 7.80-7.95 (m, 4H), 8.66 (s, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.8, 112.5, 113.8, 117.0, 120.0, 122.1, 124.8, 126.6, 127.0, 127.6, 129.2, 130.0, 132.5, 133.7, 136.2, 137.3, 142.5, 167.0, 168.2, 170.0, 172.8; Anal. calcd for C23H17N3O4.0.1H2O: C, 68.86; H, 4.32; N, 10.47. Found: C, 68.73; H, 4.01; N, 10.36.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8]([C:10]2[N:11]=[CH:12][N:13]([CH3:15])[CH:14]=2)=[O:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.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.C(O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:16]([CH3:17])[CH3:18])[C:8]([C:10]2[N:11]=[CH:12][N:13]([CH3:15])[CH:14]=2)=[O:9])=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CC(C)N(Cc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1)C(=O)c1cn(C)cn1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1ccc(F)c(-c2ccccn2)c1)C(=O)c1cn(C)cn1
Temperature: 150 °C
Yield: 28.5 %

Procedure:
A mixture of N-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1-methyl-N-(propan-2-yl)-1H-imidazole-4-carboxamide (100 mg), 2-bromopyridine (47 mg), tetrakis(triphenylphosphine)palladium (29 mg), potassium carbonate (69 mg), dimethylformamide (1.0 mL) and ethanol (0.5 mL) was stirred under irradiation with microwave while heating at 150° C. for 50 min. After the mixture was diluted with ethyl acetate, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, and then washed with water and brine. The organic phase was collected and dried over sodium sulfate, the desiccant was filtered off and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=75:25-0:100) and (silica gel cartridge, chloroform:methanol=100:0-98:2) to afford the title compound (25 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29](=[O:81])[C:30]([CH:71]([N+:78]([O-])=O)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([CH:61]([N+:68]([O-])=O)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43](=[O:60])/[CH:44]=[CH:45]/[C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[C:48]([O:58][CH3:59])[CH:47]=2)=[O:32])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Zn]>[CH3:59][O:58][C:48]1[CH:47]=[C:46](/[CH:45]=[CH:44]/[C:43]([O:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:31](=[O:32])[C:30]([CH:61]([NH2:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)([CH:71]([NH2:78])[C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[C:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:17](=[O:18])/[CH:16]=[CH:15]/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:81])=[O:60])[CH:51]=[CH:50][C:49]=1[O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCCOc1ccc(/C=C/C(=O)OCCCCCCCCOC(=O)C(C(=O)OCCCCCCCCOC(=O)/C=C/c2ccc(OCCCCC)c(OC)c2)(C(c2ccccc2)[N+](=O)[O-])C(c2ccccc2)[N+](=O)[O-])cc1OC
Agent: [Zn]
Product: CCCCCOc1ccc(/C=C/C(=O)OCCCCCCCCOC(=O)C(C(=O)OCCCCCCCCOC(=O)/C=C/c2ccc(OCCCCC)c(OC)c2)(C(N)c2ccccc2)C(N)c2ccccc2)cc1OC

Procedure:
Preparation can be carried out analogously to Synthetic Example 1 using 1.07 g (1.00 mmol) of bis [8-({(2E)-3-[3-methoxy-4-(pentyloxy)phenyl)prop-2-enoyl}oxy)octyl]2,2-bis(nitrobenzyl)malonate, 1.62 g (6.00 mmol) Ferric chloride hexahydrate and 0.65 g (10.00 mmol) Zinc powder yield bis [8-({(2E)-3-[3-methoxy-4-(pentyloxy)phenyl)prop-2-enoyl}oxy)octyl]2,2-bis(aminobenzyl)malonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13](=[CH2:18])[C:14]([O:16][CH3:17])=[O:15].[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1>CN(C=O)C.CN(C)C(=N)N(C)C>[CH3:31][C:28]([O:27][C:26]([NH:25][CH:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[C:14]([O:16][CH3:17])=[O:15])[CH2:24][CH2:23]1)=[O:32])([CH3:29])[CH3:30]
Reactant: C=C(C(=O)OC)c1ccnc2ccc(OC)nc12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(CN1CCC(NC(=O)OC(C)(C)C)CC1)c1ccnc2ccc(OC)nc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate (2.53 g, 10.37 mmol) in DMF (4 ml) and tetramethylguanidine (0.1 ml) was added 1,1-dimethylethyl 4-piperidinylcarbamate (2.08 g, 10.37 mmol). The reaction was stirred for 1 hour at 70° C. after which time the solvent was evaporated. The residue was chromatographed on silica eluting with a gradient of 5% methanol in dichloromethane affording the desired compound as a yellow solid (2.66 g, 58%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[CH3:14][C:15]1[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[CH:4][CH:3]=2)=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc(-c2ccc(I)cc2)n1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)cc2)n1

Procedure:
Example 25 was prepared using 5-(4-iodophenyl)-3-methyl-[1,2,4]oxadiazole (Intermediate 12) and N-[4-methyl-3-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 25) using DMF as the solvent.