Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:60])([F:59])[CH2:49][C:50]1[N:54]2[CH2:55][CH2:56][NH:57][CH2:58][C:53]2=[N:52][N:51]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]2[C:50]([CH2:49][C:48]([F:47])([F:59])[F:60])=[N:51][N:52]=[C:53]2[CH2:58]1)=[O:5]
Reactant: FC(F)(F)Cc1nnc2n1CCNC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(nnc2CC(F)(F)F)C1
Reaction time: 12 h
Yield: 22 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (801 mg, 2.69 mmol) was dissolved in 25 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.27 g, 3.36 mmol), crude 3-(2,2,2-trifluoro ethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 26b (460 mg, 2.24 mmol) and N, N-diisopropylethylamine (0.8 mL, 4.48 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O and extracted with ethyl acetate (30 mL×3). The organic phase was combined, concentrated under reduced pressure, added with 30 mL of ethyl acetate, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[3-(2,2,2-trifluoroethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 26 (240 mg, yield 22.1%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.CS(CCC[N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=O)=O>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C37H47N4O4SCl2 [(M+H)+] 713.2690, observed 713.2687.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:22])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[CH2:20]Cl)[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:23][NH:24][CH2:25][CH2:26][CH3:27]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:22])[N:10]([CH3:11])[C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[CH2:20][N:24]([CH3:23])[CH2:25][CH2:26][CH3:27])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](/C=C/CCl)CC1
Reactant: CCCNC
Solvent: CO
Product: CCCN(C)C/C=C/[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 80 mg (0.23 mmol) of trans-(1E)-[4-(3-Chloro-propenyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester in 4.3 ml of methanol was treated with 0.24 ml (2.34 mmol) N-methylpropylamine and stirred over night at RT. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 95:5) gave 46 mg (52%) of trans-(1E)-Methyl-{4-[3-(methyl-propyl-amino)-propenyl]-cyclohexyl}-carbamic acid 4-chloro-phenyl ester, MS: 379 (MH+, 1Cl).
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].I[CH3:14]>CN(C=O)C>[CH3:14][O:1][CH:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(O)CC(=O)OC
Reactant: CI
Solvent: CN(C)C=O
Product: COC(=O)CC(CC(=O)OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of dimethyl 3-hydroxypentanedioate (9 g, 51.1 mmol) in DMF (70 mL) was added Ag2O (35.5 g, 154.3 mmol) and iodomethane (48.2 g, 339.2 mmol) under ice-cooling. The mixture was stirred at room temperature overnight. The mixture was filtrated and the filtrate was washed with water. Ether was added and the organic layer was dried and concentrated to give the crude product, which was purified by column chromatography to give dimethyl 3-methoxypentanedioate (8 g, 82%). 1H-NMR (CDCl3): 2.48 (m, 4H), 3.21 (m, 3H), 3.50 (m, 6H), 3.85 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:6]=2[O:5]1)[CH3:2].[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C=O)C>[CH2:18]([O:13][C:12]1[C:6]2[O:5][CH:4]([O:3][CH2:1][CH3:2])[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1)[CH:17]=[CH2:16]
Reactant: CCOC1Oc2cccc(O)c2O1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cccc2c1OC(OCC)O2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 37 (4.0 g, 22.0 mmol) in DMF (7 mL) was added dropwise over 5 min to a suspension of sodium hydride (1.32 g, 33.0 mmol 60% dispersion in oil) in DMF (15 mL) at 0° C. The reaction mixture was stirred at this temperature for 15 min, then allyl bromide (2.93 g, 2.09 mL, 24.2 mmol) was added and the reaction mixture was allowed to warm to rt over 16 h. The reaction mixture was then cooled to 0° C., water was added dropwise, then the reaction mixture was extracted with t-BuOMe (3×). The organic phase was washed successively with water and brine, dried (Na2SO4) and evaporated to dryness to give 4.8 g of crude product. Purification by column chromatography (SiO2 2:98 EtOAc:cyclohexane) gave 38 compound (3.3 g, 68%):
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][N:13]2[CH2:17][CH2:16][NH:15][C:14]2=[N:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:15]2[CH2:16][CH2:17][N:13]([CH:12]=[CH:11][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:10][CH:9]=3)[C:14]2=[N:18][N+:19]([O-:21])=[O:20])=[CH:27][N:26]=1
Reactant: O=[N+]([O-])N=C1NCCN1C=Cc1ccc(OCC(F)(F)F)cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])N=C1N(C=Cc2ccc(OCC(F)(F)F)cc2)CCN1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture comprising 5.0 g of 1-{4-(2,2,2-trifluoroethoxy)phenylvinyl}-2-nitroiminoimidazolidine, 5.8 g of 2-chloro-5-chloromethylpyridine, 8.4 g of potassium carbonate and 30 ml of dimethylsulfoxide was stirred at 60° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=4/1) to give 4.9 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-{4-(2,2,2-trifluoroethoxy)phenylvinyl}-imidazolidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:15][C:16]([O:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[C:20]1([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:18][C:16]([CH2:15][N:5]2[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]2)=[O:17])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(CBr)OC(c1ccccc1)c1ccccc1
Reactant: Oc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1
Yield: 68.9 %

Procedure:
1.37 g of 4-hydroxypyridine was dissolved in 16 ml of THF, then 1.63 g of potassium tert-butoxide was added and reacted overnight. Thereafter, 3.12 g of diphenylmethyl bromoacetate was added and reacted for 6 hours. After the reaction, the solvent was removed, the residue was dissolved in chloroform and washed with water. This was dried over magnesium sulfate, the solvent was removed, and the residue was purified on silica gel chromatography using chloroform-methanol (20:1) to obtain 2.25 g of the title compound (55%).
Reaction SMILES: [Cl:1]CCl.[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17].S(Cl)(Cl)=O.Cl>CN(C)C=O>[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][C:8]([C:9]([Cl:1])=[O:10])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: ClCCl
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Temperature: 40 °C

Procedure:
In a reactor 68 kg dichloromethane, 20 kg 5-nitro-vanillic acid of example 1b, 76 gram of N,N-dimethylformamide and 13.4 kg (8 L) thionyl chloride, was charged at 20.2° C. The mixture was heated to 40° C. until all the starting material dissolved and the evolution of HCl and SO2 stopped. When all the starting material was consumed 5-10 L dichloromethane was distilled off at normal pressure at 40° C. then the mixture was cooled to 20-25° C. and the distillation was continued until dry under vacuum at 40° C. The evaporation residue was dissolved in 36 kg dry THF. The THF solution was used in Example 4d.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.C(N(CC)CC)C.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:49])=[O:48])[CH:41]=[CH:40]2>CN(C=O)C>[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:51][CH2:52][N:53]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:15][CH:14]=3)[CH2:54][CH2:55]1)(=[O:48])=[O:49])[CH:41]=[CH:40]2
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccccn2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
4-(2-Pyridyl)benzoic acid (199 mg,1 mmol) was suspended in DMF (5 mL) and triethylamine (0.14 mL, 1 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes then cooled to 5° C. Carbonyl diimidazole (162 mg, 1 mmol) was added and the reaction mixture allowed to warm slowly to room temperature over one hour. 1-(6-Bromonaphth-2-ylsulphonyl)piperazine hydrochloride (393 mg, 1 mmol) was added as a solid in one portion and the reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The crude product was dissolved in ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate solution (2×50 mL). The tube organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting off white solid was subjected to chromatography (SiO2; 100% EtOAc) to yield 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-pyridyl)benzoyl]piperazine as a white solid (92 mg); 1H NMR (DMSO-d6) δ=3.09 ppm (s,4H), δ=3.62 ppm (s,4H), δ=7.37 ppm (t,1H), δ=7.51 to 7.99 ppm (m,4H), δ=7.42 and 8.08 ppm (dd,4H), δ=8.17 ppm (dd,2H), δ=8.40 ppm (d,1H), δ=8.47 ppm (s,1H), δ=8.66 ppm (dd,1H); MS (M+H)+ 536.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]4[CH2:27][CH:26]([OH:28])[CH2:25]4)=O)[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1.[B].O1CCCC1.[Cl-].[NH4+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:24]4[CH2:27][CH:26]([OH:28])[CH2:25]4)[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: O=C(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N1CC(O)C1
Agent: [B]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1CN(Cc2cccc3nc4n(c23)CCCN4c2ccc(Cl)cc2Cl)C1
Temperature: 70 °C
Reaction time: 13 h
Yield: 63.2 %

Procedure:
To a suspension of 1-{[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]carbonyl}azetidin-3-ol (150 mg, 0.359 mmol) was added boron-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran, 1.8 mL, 1.8 mmol), and the mixture was stirred at 70° C. for 13 hr. To the mixture was added aqueous saturated ammonium chloride, and the mixture was stirred at 70° C. for 20 min. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was washed with ethanol to give the title compound as a colorless powder (91.5 mg, 0.227 mmol, 63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34].Cl.[C:39]1([S:45]([CH2:48][CH2:49][NH2:50])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=[CH:28][C:29]([NH:50][CH2:49][CH2:48][S:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)(=[O:47])=[O:46])=[O:30])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][C:8]=1[Cl:34]
Reactant: O=C(O)C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: NCCS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1)NCCS(=O)(=O)c1ccccc1

Procedure:
Prepared according to Procedure (I) utilizing 3-(5-{4-[4-(3-fluorobenzyloxy)-3-chloroanilino]-6-quinazolinyl}-2-furyl)-2-propenoic acid (0.25 g, 0.45 mmol), 2-(phenylsulfonyl)-ethylamine hydrochloride (0.30 g, 1.36 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.26 g, 1.36 mmol) and diisopropylethylamine (0.55 mL, 3.18 mmol) in acetonitrile. Electrospray MS m/z 683 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.[CH:18]#[C:19][CH3:20]>CS(C)=O.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:18]([C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1)#[C:19][CH3:20]
Reactant: CCOC(=O)c1cc(Br)cnc1C(=O)OCC
Reactant: C#CC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC#Cc1cnc(C(=O)OCC)c(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 3 g of 5-bromo-pyridine-2,3-dicarboxylic acid, diethyl ester, 0.1 g cuprous iodide and 0.7 g bis(triphenylphosphine)palladium(II)chloride in 40 mL dimethyl sulfoxide and 12 mL triethylamine is cooled to 10°, and 10 mL of liquid propyne is added. The reaction is stirred at room temperature thereafter for 16 hours, then is poured onto water and extracted with methylene chloride. The organic phase is washed with dilute hydrochloric acid, then water, then brine, and dried. Concentration in vacuo, and chromatography of the residue on silica gel using ether-hexane mixture affords the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.II.FC(F)(F)C(O[I:37](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([I:37])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: COCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCOC)c1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCOc1cc(OCOC)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1I
Temperature: -30 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Methyl 3,5-bis (methoxymethoxy)-2-(4-methoxybenzoyl)phenylacetate (0.75 g, 1.9 mmol) obtained in Example 134, Step 2 was dissolved in dichloromethane (20 mL). The resulting solution was cooled to −30° C., and iodine (0.47 g, 1.9 mmol) and [bis(trifluoroacetoxy)iodo]benzene (0.8 g, 1.9 mmol) were successively added thereto in an atmosphere of argon, followed by stirring for 2 hours. To the reaction mixture was added a saturated aqueous solution of sodium thiosulfate, and the mixture was further stirred for one hour, while the temperature was raised to room temperature. To the reaction mixture was added water for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting, residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/2) to obtain methyl 3,5-bis(methoxymethoxy)-2-iodo-6-(4-methoxybenzoyl)phenylacetate (0.95 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:12][C:13](=[O:18])[CH2:14][N:15]=[N+]=[N-])[CH3:11].[O-]CC.[NH4+].[Cl-]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[NH:15][C:4]2[C:3]([CH3:9])=[C:2]([Cl:1])[S:6][C:5]=2[CH:7]=1)=[O:18])[CH3:11]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1cc(C=O)sc1Cl
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2sc(Cl)c(C)c2[nH]1
Temperature: 10 °C

Procedure:
5-chloro-4-methyl-thiophene-2-carbaldehyde was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester was added as ethanol solution (1 M of ester) to −20° C. ethoxide solution; allow to warm to 10° C. over 2 h, 10° C. 2 h; reaction poured into cold saturated aqueous NH4Cl; after ether extraction, acrylate organic phase washed with water until aqueous phase was neutral; solution of crude acrylate added to refluxing xylenes over 5 min and then heated at reflux).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]1=[O:16])([OH:3])=[O:2].[CH3:17]O.S(=O)(=O)(O)O>O>[CH3:17][O:2][C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[O:15])[C:6]1=[O:16])=[O:3]
Reactant: CO
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of 1.0 g (4,5 mmol) 1-carboxymethylquinoxaline-2,3(1H,4H)-dione, 15 ml dry methanol and 0,2 ml concentrated sulfuric acid was stirred at 80° C. for 1 h. After cooling to 25° C. the reaction mixture was poured in water and made alkaline. The precipitate was filtered off and recrystallized (acetone) to give 0.22 g (21%) 1-methoxycarbonylmethylquinoxaline-2,3(1H,4H)-dione. M.p. 269° C. 1H-NMR (DMSO-d6 ): 12.0 (1H, broad s), 7.1 (4H, s), 4.9 (2H, s), 3.7 (3H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:22]([O:24]CC)=[O:23])[CH:14]=[C:15]([CH:21]=3)[C:16]([O:18]CC)=[O:17])[N:9]=2)[CH:4]=[CH:3][C:2]=1[C:27]1[CH:28]=[C:29]([C:38]([O:40]CC)=[O:39])[CH:30]=[C:31]([CH:37]=1)[C:32]([O:34]CC)=[O:33]>C1COCC1.CO.[OH-].[Na+]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:21]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=[C:13]([CH:12]=3)[C:22]([OH:24])=[O:23])[N:9]=2)[CH:4]=[CH:3][C:2]=1[C:27]1[CH:37]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=[C:29]([CH:28]=1)[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)c1cc(C(=O)OCC)cc(-c2ccc3ccc(-c4cc(C(=O)OCC)cc(C(=O)OCC)c4)nc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(C(=O)O)cc(-c2ccc3ccc(-c4cc(C(=O)O)cc(C(=O)O)c4)nc3n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of tetraethyl 5,5′-(1,8-naphthyridine-2,7-diyl)diisophthalate was dissolved in 60 mL of mixed solvent of THF and MeOH (v/v=1:1), 20 mL of 2N NaOH aqueous solution was added. The mixture was stirred at room temperature overnight. After the organic phase was removed, the aqueous phase was acidified with dilute hydrochloric acid to give white precipitate, which was filtered and washed with water several times. Yield: 1.5 g, 94%. 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, 2H), 8.62 (s, 2H), 8.68 (d, 2H), 9.10 (s, 4H).
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:3].C(C1C=C(O)C(=CC=1)O)(C)(C)C.CC1C=CC=CC=1C>O>[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[CH2:3]
Reactant: CC(O)c1ccc(-c2ccc(C(C)O)cc2)cc1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: O
Solvent: Cc1ccccc1C
Product: C=Cc1ccc(-c2ccc(C=C)cc2)cc1

Procedure:
The mixture of 5.00 g (0.0206 mole) of 4,4'-di-(1-hydroxyethyl)biphenyl (DHEBP), 0.0050 g (0.1% of DHEBP weight) of 4-tert-butyl catechol, 00542 g (1.08% of DHEBP weight or 3.00 mmol/L) of TSA, and 90 mL of o-xylene was heated at the boiling temperature for 1 hour. Water released during the dehydration was azeotroped from the system. Then, the reaction mixture was treated as described in Example 1. The yield of the unsaturated composition riched with 4,4 '-divinylbiphenyl (DVBP) was 4.10 g (96.5% of theor.). According to reversed phase chromatography, the content of components was as follows, wt-%: Monomer M1 (DVBP) 89, its unsaturated dimer 8.5, its insaturated trimer 2%, tetramers and higher oligomers <0.5%. The pure DVBP (purity was >99.5%), mp 150-153° C. was obtained by sublimation of the monomer at 160° C. for 1 hour under vacuum (1-2 mm Hg).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.[F:13][C:14]([F:34])([F:33])[C:15]1[CH:32]=[CH:31][CH:30]=[CH:29][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])=[O:18]>O1CCCC1.CCCCCC>[OH:18][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28])([C:16]1[CH:29]=[CH:30][CH:31]=[CH:32][C:15]=1[C:14]([F:33])([F:34])[F:13])[CH2:2][C:1]#[N:4]
Reactant: O=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(O)(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.02 h

Procedure:
A stirred solution of diisopropylamine (4.02 mL) in dry tetrahydrofurane (30 mL) under argon was treated dropwise with 1.6M n-butyl lithium in hexane (18 mL). The reaction was kept at -5° C. during the addition and for 15 minutes thereafter, then it was cooled to -78° C. and a solution of 2,2'-bis(trifluoromethyl)benzophenone (8.0 g) in tetrahydrofurane was added at such a rate that the reaction temperature did not exceed -65° C. The mixture was stirred at -78° C. for 1 minutes, then it was allowed to slowly equilibrate to room temperature over 30 minutes. After the solvents were removed under reduced pressure, the residue was treated with water (100 mL) and the resulting solid was filtered off, washed with water and dried. Crystallization of the solid from dichloromethanehexane furnished 7.72 g of 3-hydroxy-3,3-bis[2-(trifluoromethyl)phenyl]-propanenitrile, mp 168°-170° C. A sample was recrystallized from the same solvent system to give the analytical specimen, mp 171°-172° C.