Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13](=O)[C:14]([CH3:20])([CH3:19])[C:15](OC)=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].O.[NH2:23][NH2:24]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[C:14]([CH3:20])([CH3:19])[C:15](=[O:16])[NH:23][N:24]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(C(=O)C(C)(C)C(=O)OC)cc1OCC
Reactant: NN
Solvent: O
Product: CCOc1ccc(C2=NNC(=O)C2(C)C)cc1OCC

Procedure:
Prepared analogously as described for example C1 using methyl 3-(3,4-diethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D2) and hydrazine hydrate as starting compounds.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[N:12]=1.CCN(C(C)C)C(C)C>CCO>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[CH:14]=[C:13]([C:18]([F:21])([F:19])[F:20])[N:12]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 70 °C
Reaction time: 22 h
Yield: 51.5 %

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (1.42 g, 11.5 mmol), 2,4-dichloro-6-(trifluoromethyl)pyrimidine (2.50 g, 11.5 mmol), DIPEA (4.05 mL, 23.0 mmol), and anhydrous EtOH (35 mL) was stirred at 70° C. under N2 for 22 h. The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc and the organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Trituration with DCM afforded 1.80 g (51.5%) of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)pyrimidin-4-amine (186) as a white solid: 1H NMR (400 MHz, DMSO-d6): δ 12.35 (br d, J=30.2 Hz, 1H), 10.97 (s, 1H), 8.14 (s, 0.50H, rotamer), 7.13 (s, 0.50H, rotamer), 6.38 (s, 0.50H, rotamer), 5.73 (s, 0.50H, rotamer), 1.91 (s, 1H), 0.98-0.90 (m, 2H), 0.70 (q, J=5.5 Hz, 2H); MS (ESI) m/z=304.2/306.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].IC>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH3:26])[C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N(C)c2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Yield: 76.8 %

Procedure:
Following general procedure F and using 4-[(3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 16, 0.12 g, 0.35 mmol), potassium carbonate (0.49 g, 3.5 mmol) and iodomethane (0.50 g, 3.5 mmol) in 2 mL of anhydrous N,N-dimethylacetamide, the title compound (0.095 g, 80%) was obtained as a pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 2H, J=9.1 Hz), 6.81 (d, 1H, J=2.3 Hz), 6.78 (d, 1H, J=2.3 Hz), 6.63 (d, 2H, J=9.1 Hz), 4.31 (q, 2H, J=7.1 Hz), 4.28 (s, 2H), 3.31 (s, 3H), 2.59 (q, 2H,J=7.6 Hz), 1.35 (t, 3H, J=7.1 Hz), 1.33 (s, 6H), 1.22 (t, 3H, J=7.6 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:36]([C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)=[CH:39][CH:38]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1ccnc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: Cn1ccnc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-2-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.105 g, 0.26 mmol, 1 eq) in EtOH (6 mL) and DMF (0.9 mL), 4-(morpholinomethyl)-benzaldehyde (0.060 g, 0.29 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.78 mL, 0.78 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature, and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained as a solid after trituration with diethyl ether (0.027 g, 18%); 1H-NMR (500 Mz, DMSO-d6): δ 2.34-2.42 (m, 4H), 2.56-2.64 (m, 4H), 3.53 (s, 2H, morpholine N(CH2)2), 3.56-3.68 (m, 10H), 3.72 (s, 3H, imidazole Me), 6.78 (d, J=1.5 Hz, 1H, imidazole 4-H), 7.11 (d, J=1.5 Hz, 1H, imidazole 5-H), 7.47 (d, J=8.0 Hz, 2H, ArH), 8.13 (d, J=8.0 Hz, 2H, ArH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.23 min—551/553 [(M+H+), Br isotopic pattern, 100%]. ESI-HRMS: Found: 551.1884, calculated for C26H32BrN8O (M+H)+: 551.1882.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])=[N:5]2.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([NH:14][C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:32][CH:31]=3)=[O:35])[CH:15]=[CH:16][CH:17]=1)=[N:5]2
Reactant: Nc1cccc(Oc2ccc3nccn3n2)c1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(Oc2ccc3nccn3n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg, 0.50 mmol) and triethylamine (0.040 mL, 0.29 mmol) in tetrahydrofuran (10 mL) was added 4-(trifluoromethyl)phenyl isocyanate (0.100 mL, 0.70 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was precipitated from methanol to give the title compound (103 mg, 50%) as a white powder.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([NH2:17])=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClS([N:22]=[C:23]=[O:24])(=O)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:1]1([C:7]2[S:8][C:9]([NH:17][C:23]([NH2:22])=[O:24])=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1nc(-c2ccccc2)sc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccccc2)sc1NC(N)=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of ethyl 2-phenyl-5-aminothiazole-4-carboxylate (116 mg, 1.0 eq) in dichloromethane (3 ml) at −78° C. was added chlorosulfonyl isocyanate (0.06 ml, 1.3 eq) dropwise (Redman et al J. (2000) Org. Lett. 2:2061-2063). The reaction was slowly warmed to room temperature and stirred for 40 minutes. The reaction was concentrated. To the residue was added 6N HCl (2.5 ml) and mixture was heated to 100° C. for 20 minutes. Reaction mixture was allowed to cool down to room temperature, and was neutralized with saturated aq. NaHCO3. Solid was collected by filtration to yield ethyl 2-phenyl-5-ureidothiazole-4-carboxylate 63 as a beige solid which was used in the next reaction without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[C:13]([C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C#N)c1cccc(OC)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)(Cc1ccccc1)c1cccc(OC)c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (7.80 ml, 54.7 mmol) in 100 ml dry tetrahydrofuran at −78° C. was added n-butyl lithium (34.2 ml, 54.7 mmol) and stirred for 1 h while the reaction mixture was allowed to warm up to −40° C. A solution of ethyl 2-cyano-2-(3-methoxyphenyl)acetate (10 g, 45.6 mmol) in 100 ml dry tetrahydrofuran was added and the mixture stirred for 30 min. Then (bromomethyl)benzene (8.13 ml, 68.4 mmol) was added and the reaction was stirred over night. The solvent was evaporated and the residue dissolved in ethyl acetate, which was washed with 10% citric acid, water and brine. The combined organic layers were dried over sodium bicarbonate, filtered and the solvent evaporated to obtain a yellow-orange oil. Purification on 120 g SiO2 using 20% ethyl acetate in cyclohexene afforded a clear colourless oil m=9.4 g (66.6%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]2)=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]>>[CH2:14]([O:16][C:17](=[O:28])[C:18](=[CH:24][NH:13][C:12]1[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:9]=[CH:10][CH:11]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]
Reactant: Nc1ccnn1Cc1ccncc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccnn1Cc1ccncc1)C(=O)OCC
Yield: 64 %

Procedure:
174 g of 1-(4-picolyl)-5-aminopyrazole and 216 g of ethoxymethylene malonic acid diethyl ester are heated with stirring at 140°, until the theoretical amount of alcohol has distilled off. The reaction mixture crystallizes on cooling. Recrystallization from ethyl acetate yields 220 g of [[[1-(4-picolyl)-5-pyrazolyl]amino]methylene]malonic acid diethyl ester (65%), m.p. 95°-97°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2ccc(F)c(Cl)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(F)c(Cl)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a stirred mixture solution of 4-[(3-chloro-4-fluoro-benzylidene)-amino]-benzoic acid ethyl ester (3.1 g, 10.2 mmol) and ytterbium(III) triflate hydrate (944 mg, 1.5 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.93 mL, 10.2 mmol) and water (0.2 mL, 10.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid ethyl ester (3.8 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C20H21ClFNO3 (M+H)+: 378.85, observed: 360.1 & 378.1.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]=[CH2:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].[C:29]1([Mg]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([OH:13])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]=[CH2:26])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6]
Reactant: Br[Mg]c1ccccc1
Reactant: C=CC=CCCOc1ccc(C(=O)c2ccc(OCCC=CC=C)cc2)cc1
Solvent: C1CCOC1
Product: C=CC=CCCOc1ccc(C(O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
Compound 29 (5.96 g, 15.91 mmol) was dissolved in anhydrous THF (133 mL) with slight heating. Phenylmagnesium bromide (32 mL of a 1.0M solution in THF, 32 mmol) was added to the solution and the mixture was stirred at room temperature under argon for 5 hours and evaporated to dryness under vacuum. The residue was redissolved in dichloromethane and washed with a saturated solution of ammonium chloride, followed by water. The organic phase was dried (MgSO4), concentrated in vacuo, and purified by column chromatography (silica gel; hexane/CH2Cl2, 1/9) to yield 4.45 grams (62%) of compound 30 as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ2.45-2.56 (m, 4H), 3.98 (t, J=6.6 Hz, 4H), 5.01 (dd, J=1.5, 9.9 Hz, 2H), 5.14 (dd, J=1.5, 16.5 Hz, 2H), 5.73-5.87 (m, 2H), 6.12-6.41 (m, 4H), 6.25 (s, 1H), 6.84 (d, J=6.9 Hz, 4H), 7.06 (d, J=7.8 Hz, 4H), 7.15-7.33 (m, 5H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][Si:13]([CH2:16][Mg]Cl)([CH3:15])[CH3:14].Cl>C(OCC)C>[Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)([OH:4])[CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: C[Si](C)(C)C[Mg]Cl
Agent: Cl
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)(CCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
8.63 g (0.05 mole) of 2-chloro-4'-fluoroacetophenone were dissolved in 60 ml of diethyl ether. The solution was stirred under a stream of nitrogen, and 200 ml (0.057 mole) of a diethyl ether solution of trimethylsilylmethylmagnesium chloride were added dropwise at such a rate that the temperature of the reaction mixture did not rise above 15° C.-20° C. The reaction mixture was then stirred for a further 1 hour at room temperature, after which it was poured into 200 ml of ice water, and its pH was adjusted to a value of 6-7 by the addition of 5% w/v aqueous hydrochloric acid. It was then extracted with 100 ml of ethyl acetate. The organic extract was washed twice, each time with 50 ml of a saturated aqueous solution of sodium chloride It was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to afford a crude oily product. This crude oily product was purified by silica gel column chromatography, using mixtures of ethyl acetate and hexane ranging from 1:10 to 1:5 by volume, to give 8.8 g (yield 67.7%) of the title compound as an oily substance.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([O:29][CH3:30])[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.C(OCC)(=O)C>[N+:26]([C:25]1[C:20]([NH:1][CH:2]([CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])=[N:21][C:22]([O:29][CH3:30])=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: NC(C(=O)O)C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(NC(C(=O)O)C(c2ccccc2)c2ccccc2)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 20.1 %

Procedure:
2.50 g (10.4 mmol) of 2-amino-3,3-diphenylpropionic acid, 0.84 g (4.3 mmol) of 2-chloro-3-nitro-6-methoxypyridine and 0.55 g (5.2 mmol) of sodium carbonate were introduced into 18 ml of DMF and 18 ml of water, and the mixture was stirred at 80° C. for 5 hours. Ethyl acetate and water were then added, and the phases were separated. The aqueous phase was acidified with 6 normal hydrochloric acid and extracted three times with ethyl acetate. After drying with MgSO4 and concentration under reduced pressure, the crude product was recrystallized from isopropanol. 0.34 g (20.1%) of a yellow powder of melting point 172-180° C. was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:8].[C:20]([N:27]1[CH:31]=[CH:30]N=[CH:28]1)(N1C=CN=C1)=[O:21].N1CC[O:35][CH2:34]C1.O>ClCCl>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:20]([N:27]2[CH2:31][CH2:30][O:35][CH2:34][CH2:28]2)=[O:21])[S:13][C:9]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Reactant: C1COCCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccn1)c1sc(NC(=O)N2CCOCC2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
Compound 186 (100 mg, 0.369 mmol) was suspended in dichloromethane (3.7 mL), and carbonyldiimidazole (89.7 mg, 554 mmol) was added thereto at room temperature, followed by stirring for 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in THF (3.7 mL). Morpholine (0.0484 mL, 554 mmol) was added to the resulting solution, followed by stirring for 2 hours at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=20:1) to afford the entitled Compound 256 (93.9 mg, 66%) as a pale yellow solid.
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: Cc1ccccc1C
Solvent: O
Product: C=Cc1ccc(-c2ccc(C=C)cc2)cc1

Procedure:
The mixture of 5.0020 g (0.02064 mole) of 4,4'-di-(1-hydroxyethyl)biphenyl (DHEBP), 0.0050 g (0.1% of DHEBP weight) of 4-tert-butyl catechol, 00742 g (1.483% of DHEBP weight or 4.11 mmol/L) of TSA, and 90 mL of o-xylene was heated at the boiling temperature for 40 minutes. 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 3.8 g (89.3% of theor.). According to reversed phase chromatography, the content of components was as follows, wt-%: Monomer M1 (DVBP) 77, its unsaturated dimer 17, its insaturated trimer 5%, tetramers and higher oligomers <1%. 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: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.O[C:29]1([C:52]2[C:60]([OH:61])=[CH:59][C:55]3[O:56][CH2:57][O:58][C:54]=3[CH:53]=2)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([CH2:38][CH2:39][N:40]2[C:48](=[O:49])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]2=[O:50])[C:30]1=[O:51]>>[OH:61][C:60]1[C:52]([CH:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH2:38][CH2:39][N:40]3[C:48](=[O:49])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:50])[C:30]2=[O:51])=[CH:53][C:54]2[O:58][CH2:57][O:56][C:55]=2[CH:59]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1c2ccccc2C(=O)N1CCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 2-{2-[3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione, the title compound was obtained (90%) as a white solid: 1H NMR (300 MHz, CD3OD) δ 10.15-10.05 (br, 1H), 8.66-8.58 (m, 4H), 8.07-7.70 (m, 4H), 7.12 (s, 1H), 7.18 (s, 1H), 6.70 (s, 1H), 6.69 (s, 1H), 5.50 (s, 1H), 4.91-4.56 (m, 4H); MS (ES+) m/z 443 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([O:25][CH:26]=[CH:27]C(OCC)=O)=[O:24])=[CH:21][CH:20]=1.[H][H]>[Pd].O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:33][CH:34]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=COC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
A solution of 4 g. 2-(ethoxycarbonyl)vinyl 4-(16-bromohexadecylamino)benzoate and 400 mg. 10% palladium-on-carbon in 100 ml. tetrahydrofuran is hydrogenated at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetonitrile to yield 2-ethoxycarbonyl)ethyl 4-(16-bromohexadecylamino)benzoate.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:10])[CH2:8][NH2:9].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:9][CH2:8][CH2:7][NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NCCNC1CCCC1
Reaction time: 48 h
Yield: 34.5 %

Procedure:
To a solution of cyclopentanone (2.000 mL, 22.6 mmol), ethylenediamine (10.860 g, 180.7 mmol), acetic acid (10.345 mL, 180.7 mmol), and 4 {acute over (Å)} molecular sieves (10 g) in anhydrous methanol (113 mL) was added sodium cyanoborohydride (2.839 g, 45.2 mmol). The mixture was stirred for 48 hrs, filtered to remove the solids, and concentrated in vacuo. The residue was dissolved in 3 N aqueous sodium hydroxide (150 mL) and extracted with methylene chloride (3×300 mL). The combined organic layers were washed with basic saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to give the crude product. The material was vacuum distilled to give the desired product as a clear liquid (1.0 g, 35%). 1H NMR (300 MHz, CDCl3) δ 3.08-2.99 (quint, 1H, J=6.8 Hz), 2.80-2.76 (t, 2H, J=5.9 Hz), 2.65-2.61 (t, 2H, J=5.9 Hz), 1.87-1.77 (m, 2H), 1.72-1.60 (m, 2H), 1.57-1.46 (m, 2H), 1.35-1.24 (m, 5H).
Reaction SMILES: [C:1](O)(=[O:4])[CH:2]=[CH2:3].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[F:22][C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>ClCCl.O>[C:1]([N:32]1[CH2:31][CH2:30][CH:29]([CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:36][CH:35]=2)[CH2:34][CH2:33]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: Fc1ccc(OCC2CCNCC2)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CCC(COc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.8 %

Procedure:
To a solution of acrylic acid (34 μL, 0.49 mmol) in dichloromethane (2.4 mL) cooled at 0° C. was added 4-methylmorpholine (134 μL, 1.22 mol) and isobutyl chloroformate (74 μL, 0.57 mmol). The solution was stirred 15 minutes at 0° C. and then 4-[(4-fluorophenoxy)methyl]piperidine hydrochloride (100 mg, 0.41 mmol) was added. The mixture was stirred at room temperature overnight, diluted with water (7 mL) and extracted twice with DCM (2×5 mL). The combined organic phases were washed with water, dried over sodium sulphate and concentrated in vacuo. The residue obtained was purified by preparative TLC (eluent: dichloromethane/MeOH 95/5) to give the title compound (30 mg, 28%) as a yellow oil.