Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:18]([O:9][C:5]1[CH:4]=[C:3]([OH:10])[C:2]([Br:1])=[CH:7][C:6]=1[Br:8])(=[O:20])[CH3:19]
Reactant: Oc1cc(O)c(Br)cc1Br
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(O)c(Br)cc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
Under nitrogen, 4,6-dibromo-1,3-benzenediol (10.58 gram, 39.5 millimoles, 1.0 equivalent) and triethylamine (11.0 milliliter, 7.99 grams, 79.0 millimoles, 2.0 equivalents) dissolved in dichloromethane (80 milliliters) were cooled to 0° C. Acetyl chloride (3.09 milliliters, 43.4 millimoles, 1.1 equivalents) were added over the course of 17 minutes. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was worked up by removal of the volatiles by rotary evaporation. The solid residue was taken up in 100 milliliters ethyl acetate. The mixture was allowed to stir for 5 minutes, and the precipitate was removed by filtration. The product was purified by gradient flash column chromatography (ethyl acetate in hexane, 0 to 40%). The product was obtained in the form of a colorless solid (6.73 grams, 21.7 millimoles, 55%). m.p.: 121.3° C.; 1H-NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 6.85 (s, 1H), 5.59 (s, 1H), 2.34 (s, 3H); 13C NMR (101 MHz, THF) δ 168.12, 155.60, 149.52, 136.49, 112.77, 108.40, 106.30, 20.59; FTIR 570, 647, 690, 707, 768, 842, 872, 920, 1025, 1060, 1168, 1206, 1240, 1367, 1394, 1489, 1580, 1599, 1718, 2936, 2993, 3082, 3296 cm−1; UV/Vis: 221, 229 (overlapping), 292 nm; ESI/MS/MS of m/z=309: 309 [M79Br/81Br-H]−, 267 [M79Br/81Br—(CH2C═O, H)]−, 81 [81Br]−, 79 [79Br]−; HRMS (ESI−): calc. for C8H5Br2O3− [M-H]− 306.8605, found 306.8622.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](O)=[O:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[N:21]1[C:26](C)=CC=C[C:22]=1C.CNC>ClCCl.CN(C)C=O>[Cl:1][C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:7](=[O:8])[N:21]([CH3:26])[CH3:22])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)O
Reactant: Cc1cccc(C)n1
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Cl)nc1C(=O)N(C)C
Temperature: 45 °C
Yield: 76 %

Procedure:
To a stirred solution of 2-chloro-5 (ethoxy carbonyl)-1,3-thiazole-4-carboxylic acid (Intermediate 7, 2 g, 8.01 mmol) in dry dichloromethane (20 mL) was added oxalyl chloride (1.37 mL, 16.02 mmol) and 2 drops of dry dimethylformamide. The reaction mixture was heated to 45° C. for 90 minutes. After the completion of the reaction, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in dry dichloromethane (20 mL) and was cooled to 0° C., then 2,6-lutidine (0.97 mL, 8.4 mmol) was added followed by addition of N,N-dimethylamine (2 M solution in tetra hydro furan, 4.19 mL, 8.4 mmol). After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was extracted with ethyl acetate (2×50 mL). The organic layer was washed with 1 N hydrochloric acid, water and brine (1×50 mL), and concentrated after drying over anhydrous sodium sulfate to afford 1.6 g (72.7%) of the title compound as a thick syrup.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:16])([CH3:15])[CH2:6][NH:7]C(OC(C)(C)C)=O)(=[O:3])[CH3:2].[ClH:17]>C(OCC)(=O)C>[ClH:17].[C:1]([O:4][C:5]([CH3:16])([CH3:15])[CH2:6][NH2:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)(C)CN
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-(tert-Butoxycarbonylamino)-1,1-dimethylethyl acetate (508 mg, 2.2 mmol) was dissolved in ethyl acetate (6 ml). 3 M hydrogen chloride in ethyl acetate (4 ml, 12 mmol) was added. The reaction mixture was stirred for 20 h at room temperature. The precipitation was filltered off and washed with diethyl ether (50 ml). It was dried in vacuo to give 246 mg of 2-amino-1,1-dimethylethyl acetate hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:20])/[CH:17]=[CH:18]/[CH3:19])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[O:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:2]3[N:7]=[C:6]([S:8][C:9]4[CH:10]=[C:11]([NH:15][C:16](=[O:20])/[CH:17]=[CH:18]/[CH3:19])[CH:12]=[CH:13][CH:14]=4)[CH:5]=[CH:4][N:3]=3)=[CH:32][CH:33]=2)[CH2:25][CH2:26]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: C/C=C/C(=O)Nc1cccc(Sc2ccnc(Cl)n2)c1
Product: C/C=C/C(=O)Nc1cccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Yield: 69.6 %

Procedure:
In a procedure analogous to Example 8, reaction of (E)-N-(3-(2-chloropyrimidin-4-ylthio)phenyl)but-2-enamide (103 mg, 0.26 mmol) and 4-morpholinoaniline (47 mg, 0. 26 mmol) furnished the product (81 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:21]#[N:22].Cl.N1C=CC=CC=1.[OH-].[NH4+]>>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:21]#[N:22]
Reactant: COc1ccc2cc3c(Nc4ccc(Cl)cc4Cl)c(C#N)cnc3cc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: N#Cc1cnc2cc3cc(O)ccc3cc2c1Nc1ccc(Cl)cc1Cl
Temperature: 215 °C
Reaction time: 1 h

Procedure:
According to the procedure of example 105, the reaction mixture of 373.9 mg (0.954 mmol) of 4-(2,4-dichloroanilino)-8-methoxybenzo[g]quinoline-3-carbonitrile and 10 g of pyridine hydrochloride is stirred at 215° C. for 1 hour under N2. After cooling, the mixture is neutralized with 40 mL of a 3% ammonium hydroxide solution and stirred for 0.5 hour. The separated solid is filtered off and washed with water and ether. After drying in vacuo, this yields 333.4 mg (92.6%) of 4-(2,4-dichloroanilino)-8-hydroxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp 267-269° C.
Reaction SMILES: [C:1]([O-:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[Na+].[C:15]([O:25][CH2:26][CH:27]1[O:29][CH2:28]1)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O>[OH:7][C:6]1[CH:5]=[C:4]([CH:3]=[CH:2][C:1]([O:13][CH2:28][CH:27]([OH:29])[CH2:26][O:25][C:15](=[O:24])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])[CH:11]=[CH:10][C:8]=1[OH:9]
Reactant: O=C(C=Cc1ccccc1)OCC1CO1
Reactant: O=C([O-])/C=C/c1ccc(O)c(O)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(C=Cc1ccc(O)c(O)c1)OCC(O)COC(=O)/C=C/c1ccccc1
Reaction time: 23 h

Procedure:
To a solution of sodium caffeate (210; 7.35 mmol) in DMSO (20 mL) at 60°-70° C. was added glycidyl cinnamate (130; 7.35 mmol). The resulting mixture was heated to 60°-75° C. with continuous stirring for 22-24 h and then distilled under reduced pressure to yield compound (Ie). 1H-NMR (CD3OD) δ 4.16 (s, 1H), 2.28 (s, 4H), 6.29 (d, 1H, J=16 Hz), 6.65 (d, 1H, J=16 Hz), 6.75 (d, 1H, J=8 Hz), 6.93 (1H, dd, J=8, 2 Hz), 7.03 (d, 1H, J=2 Hz), 7.37 (m, 1H), 7.38 (m, 1H), 7.55 (m), 7.59 (d, 1H, J=16 Hz), 7.72 (d, 1H, J=16 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]2=[N:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=3)=[CH:16][N:10]2[N:9]=1)=[O:6].[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:39]([O:38][C:34](=[O:37])[CH:35]=[CH:36][C:2]1[CH:33]=[CH:32][CH:31]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]3=[N:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:18]=4)=[CH:16][N:10]3[N:9]=2)[CH:3]=1)[CH3:40]
Reactant: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(Br)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc(C(=O)Nc2ccc3nc(-c4ccc(C)c(NC(=O)C(C)(C)C)c4)cn3n2)c1
Temperature: 110 °C
Yield: 30.4 %

Procedure:
To a mixture of 3-bromo-N-[2-[3-(2,2-dimethylpropanoylamino)-4-methyl-phenyl]imidazo[2,1-f]pyridazin-6-yl]benzamide (0.126 g, 0.25 mmol), Ethyl acrylate (0.272 mL, 2.5 mmol), palladium(II) acetate (2.8 mg, 0.01 mmol), tri(o-tolyl)phosphine (0.0152 g, 0.05 mmol) in DMF (1.45 mL) is added DIPEA (0.174 mL, 1 mmol). The mixture is degassed with N2 then sealed and heated at 110° C. for 18 hours. The reaction mixture is cooled, saturated aqueous NaHCO3 (50 mL) added and extracted with EtOAc (×3). Organic layers are combined and washed with water, NaHCO3, brine, then dried, concentrated and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.040 g). LCMS (m/z)=526.6 [M+H]+, tR=2.92 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([CH3:36])[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][C:29]=2[CH3:36])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: Cc1cc(F)ccc1B(O)O
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: [Na+]
Product: Cc1cc(F)ccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-fluoro-2-methylphenyl)boronic acid (215 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 216 mg, 67%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=O.[C:15]([NH2:18])(=[S:17])[CH3:16]>C(O)C>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([C:3]2[N:18]=[C:15]([CH3:16])[S:17][CH:2]=2)[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: CC(N)=S
Reactant: COc1ccc(C(=O)CBr)cc1OC
Solvent: CCO
Product: COc1ccc(-c2csc(C)n2)cc1OC
Yield: 99.6 %

Procedure:
Ex-69A: A solution of 2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone (0.62 g, 2.39 mmol) and thioacetamide (0.18 g, 2.39 mmol) in ethanol (30 mL) was refluxed for 2 hours and the solvent was removed under reduced pressure. The product, 4-(3,4-dimethoxy-phenyl)-2-methyl-thiazole (0.56 g, 100%) was obtained as a white solid and used without further purification. To a suspension of 4-(3,4-dimethoxy-phenyl)-2-methyl-thiazole obtained above (0.70 g, 2.97 mmol) in dichloromethane (60 mL) at 0° C. was added dichloromethyl methyl ether (0.40 mL, 4.46 mmol) followed by addition of titanium tetrachloride (1.0 M solution in dichloromethane, 8.9 mL, 8.9 mmol) dropwise. The reaction mixture was allowed to stir overnight at ambient temperature and then poured into ice. The aqueous solution was extracted with dichloromethane. The solution of dichloromethane was washed with hydrochloric acid (0.5M), saturated solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The product, 2,4-dimethoxy-5-(2-methyl-thiazol-4-yl)-benzaldehyde, was obtained as a white solid. 1H NMR (CDCl3) δ 10.33 (s, 1H), 8.67 (s, 1H), 7.56 (s, 1H), 6.52 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C@@H:7]([C:12]([OH:14])=[O:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[ClH:15].[CH3:16]O>>[ClH:15].[CH3:16][O:13][C:12]([C@@H:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:9][NH:8]1)=[O:14]
Reactant: O=C(O)[C@@H]1Cc2ccc(O)cc2CN1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1

Procedure:
To a suspension of (S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid dehydrate (109 mmol) in methanol (150 mL) was added hydrochloric acid (27 mL of 4M solution in dioxane) at r.t and the reaction mixture was refluxed for 4 h. The mixture was concentrated, resuspeneded in 150 mL of MeOH and hydrochloric acid (27 mL of 4M solution in dioxane) added. The mixture refluxed for 4 h and was concentrated under reduced pressure. The residue was triturated with ether, filtered and washed with ether to give (S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester hydrochloride salt (25.1 g). 1H NMR (400 MHz, DMSO d6): 10.1 (m, 2H), 9.62 (s, 1H), 7.03 (d, 1H), 6.7 (m, 1H), 6.26 (d, 1H), 4.48 (m, 1H), 4.21 (s, 2H), 3.77 (s, 3H), 3.17-2.96 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[C:9](=[CH2:12])[C:10]#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH:3]1[C:9](=[CH2:12])[CH:10]=[O:25]
Reactant: CC(=O)O
Reactant: C=C(C#N)C1CC(C)(C)CC1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C=O)C1CC(C)(C)CC1C
Temperature: 25 °C

Procedure:
2-(2,4,4-Trimethylcyclopentyl)acrylonitrile 5 is placed in toluene at 10° C. under an inert atmosphere. 1.2 eq. of Dibal (diisobutylaluminum hydride) are added thereto dropwise. The reaction medium is stirred at ambient temperature for a few hours and is then poured onto a 20:40:40 mixture of acetic acid, water and ice. The aqueous phase is extracted once with toluene. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product, obtained in the form of two diastereomers in proportions of 70:30, is distilled under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].Cl.[Cl:38][CH2:39][CH2:40][CH2:41][NH2:42].C(N(CC)CC)C>CN(C=O)C>[Cl:38][CH2:39][CH2:40][CH2:41][NH:42][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:36])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: NCCCCl
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCCl)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 60 °C
Yield: 47.3 %

Procedure:
To 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (206 mg, 0.4 mmol) in DMF (4 mL) was added (3-chloropropyl)amine hydrochloride (78 mg, 0.6 mmol) and triethylamine (112 uL, 0.8 mmol). The mixture was heated with microwave at 60° C. for 2 hrs. The mixture was separated by flash chromatography to afford the title compound (100 mg, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH2:6])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[F:13][B-:14]([F:17])([F:16])[F:15].[H+].[N:19](OC(C)(C)C)=O>C(O)C>[F:13][B-:14]([F:17])([F:16])[F:15].[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([N+:6]#[N:19])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)cc(CC)c1N
Reactant: CC(C)(C)ON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Product: CCc1cc(Br)cc(CC)c1[N+]#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
At 0° C., to a stirred solution of commercial 4-bromo-2,6-diethylaniline (10.0 g, 43.9 mmol) in absolute ethanol (219 mL) was added 48% aq. tetrafluoroboric acid (17.2 mL), followed by tert-butyl nitrite (5.7 mL, 48.0 mmol). After 0.5 h, the reaction was poured into ice cold ether (877 mL). The resulting precipitate was washed with cold ether and dried to give 9.39 g (66%) of the title compound. 1H NMR: consistent.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(S[C:16]1[N:17]=[C:18]([OH:25])[C:19]2[S:24][CH2:23][CH2:22][C:20]=2[N:21]=1)C.O>C(O)(=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:16]3[N:17]=[C:18]([OH:25])[C:19]4[S:24][CH2:23][CH2:22][C:20]=4[N:21]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCSc1nc(O)c2c(n1)CCS2
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Temperature: 125 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
6.4 g (39 mmol) of N-phenylpiperazine (III) is placed in 2.2 mL of glacial acetic acid, heated to 125° C., then 3.2 g (15 mmol) of 2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (II) is added, and the mixture is heated to 175° C. After 1.5 hours, the resulting solid is stirred with water, suction filtered, washed with ethanol, and dried. 4.3 g product (91%) is obtained as a powder.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>CO>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]2[CH2:18][CH:17]([OH:19])[CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 40 °C
Yield: 35.9 %

Procedure:
A solution of benzhydrylamine (200 ml, 1.16 mol) and epichlorohydrin (186 ml, 1 mol. equiv.) in methanol (600 ml) was stirred at room temperature for five days and then heated at 40° C. for two days. The solvent was removed under reduced pressure, the residue dissolved in isopropyl alcohol (500 ml) and the solution heated under reflux for six hours. The solution was cooled to room temperature and the precipitate filtered off. This solid was partitioned between dichloromethane (400 ml) and saturated aqueous sodium bicarbonate solution (500 ml). The aqueous phase was extracted with dichloromethane (2×400 ml) and the combined organic phases dried over magnesium sulphate. The solution was then filtered and the solvent removed from the filtrate by evaporation under reduced pressure to give the title compound (86 g) as a crystalline solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[CH:10]=2)[CH:8]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: COc1cc(/C=C/C(=O)Nc2ccccc2)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: O=C(/C=C/c1cc(O)cc(-c2ccc3cc(O)ccc3c2)c1)Nc1ccccc1
Yield: 14 %

Procedure:
The compound is prepared by reaction of (E)-3-[3-methoxy-5-(6-methoxy-naphthalene-2-yl)phenyl]-N-phenylacrylamide (126 mg, 0.31 mmol, 1 eq) with boron tribromide solution (5 eq) according to method G. Purification by preparative thin-layer chromatography with dichloromethane/methanol 98/2 yielded the desired product in a yield of 14%, 17 mg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[S:24].Cl>O.CC(C)=O>[CH3:21][N:22]([CH3:26])[C:23](=[S:24])[O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=S)Oc1ccc(S(=O)(=O)c2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
2.36 g (0.0097 mol) of 4-[(4-hydroxyphenyl)sulfonyl]benzonitrile are added to a solution of 570 mg of potassium hydroxide in 35 ml of water. The solution is kept at room temperature for 15 minutes. After cooling to 0° C., a solution of 1.38 g of N,N-dimethylthiocarbamoyl chloride in 35 ml of acetone is added dropwise. After 4 hours, the reaction mixture is hydrolyzed in a 1 N solution of hydrochloric acid. The solution is extracted with ethyl acetate. The organic phase is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and concentrated to dryness. 3 g (yield: 100%) of the expected product are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:8]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:7][C:4]=1[CH:5]=O.[C:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:8]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:7][C:4]=1/[CH:5]=[CH:25]/[C:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[O:26]
Reactant: COCCOCCOc1cc(OC)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COCCOCCOc1cc(OC)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 61 %

Procedure:
The title compound was prepared by condensing 2-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-benzaldehyde (Ex-49A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 174–175° C., 61% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.23 (d, 2H, J=8.1 Hz), 8.05–8.11 (m, 3H), 7.91 (d, 1H, J=15.3 Hz), 7.72 (d, 1H, J=2.7 Hz), 7.52 (d, 1H, J=4.2 Hz), 7.11–7.15 (m, 1H), 6.86 (s, 1H), 4.39 (t, 2H, J=3.9 Hz), 3.99 (s, 3H), 3.89 (t, 2H, J=3.9 Hz), 3.64 (t, 2H, J=3.9 Hz), 3.48 (t, 2H, J=3.9 Hz), 3.25 (s, 3H). MS (ESI) m/z=483 ([M+H]+, 100%). Anal. Calcd. for C26H26O7S: C, 64.71; H, 5.43; S, 6.64. Found: C, 64.43; H, 5.34; S, 6.54.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)([CH3:12])([CH3:11])[CH3:10].[BH4-].[Na+]>CC#N>[C:9]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)Oc1ccccc1C=O
Reactant: NCc1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)Oc1ccccc1CNCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
2-(Aminomethyl)pyridine (0.849 g, 7.85 mmol) and 8 (1.4 g, 7.8 mmol) were added to 150 mL of CH3CN and the reaction mixture was refluxed under argon for 4 hr. After cooling down to room temperature, the solvent was removed and the residue was redissolved in MeOH. The solvent was then evaporated and NaBH4 (1.485 g, 39 mmol) was added and stirred overnight. The solvent was evaporated, followed by extraction with CH2Cl2. The CH2Cl2 extract was concentrated and purified by a silica gel column using 3% methanolic NH3 (7 M NH3 in methanol/97% CH2Cl2 as eluent to yield the desired product as a pale yellow oil (58%). 1H NMR (CDCl3) δ 8.530 (m, 1H, Ar), 7.604 (ddd, 1H, Ar), 7.330 (m, 2H, Ar), 7.128 (m, 2H, Ar), 7.027 (d, 2H, Ar), 6.969 (ddd, 1H, Ar), 3.892 (s, 2H, —CH2—), 3.837 (s, 2H, —CH2—), 2.523 (s, 1H, —CH—), 1.373 (s, 9H, —C(CH3)3). Mass Spec.=271.18 (M+H)+.