Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([CH:8]([OH:12])[CH:9]([OH:11])[CH3:10])[O:6][C:5]([CH3:14])([CH3:13])[O:4]1.I[CH2:16][C:17]([O-:19])=[O:18].[Na+].[OH-].[Na+].I[CH3:24]>O>[OH:12][CH:8]([C@H:7]1[O:6][C:5]([CH3:13])([CH3:14])[O:4][C@H:3]1[CH2:2][O:1][CH2:16][C:17]([O:19][CH3:24])=[O:18])[CH:9]([OH:11])[CH3:10]
Reactant: CI
Reactant: CC(O)C(O)C1OC(C)(C)OC1CO
Reactant: O=C([O-])CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)COC[C@@H]1OC(C)(C)O[C@@H]1C(O)C(C)O
Reaction time: 8 h
Yield: 21.8 %

Procedure:
A solution of 4-(hydroxymethyl)-5-(1,2-dihydroxypropyl)-2,2-dimethyl-1,3-dioxolane (63 g, 0.33 mol) and sodium iodoacetate (75 g, 0.36 mol) in water was treated with solid sodium hydroxide (16 g, 0.35 mol). The reaction mixture was stirred overnight and then washed with ethyl acetate and ether. The aqueous layer was concentrated. The resulting residue was dissolved in DMF (20 mL) and treated with iodomethane (37 mL, 0.6 mol). The resulting reaction mixture was stirred overnight. The reaction mixture was diluted with two volumes of salt water and extracted with ethyl acetate (6×). The combined organic layers were dried, and concentrated to give 20 g of 2-[[(4S,5R)-5-(1,2-dihydroxypropyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]ethanoic acid, methyl ester, a compound of formula (L), as a colorless viscous oil; 1H NMR (CDCl3) δ 1.27 (d, 3H), 1.38 (s, 3H), 1.48 (s, 3H), 3.57 (m, 1H), 3.77 (s, 3H), 3.8 (m, 2H), 4.13 (m, 2H), 4.4 (m, 2H) ppm.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[H][H].[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>O.CN(C)C=O.C1C=CC=CC=1>[C:1]12([O:11][C:22]3[CH:21]=[CH:20][C:19]([N+:24]([O-:26])=[O:25])=[CH:18][C:17]=3[F:16])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(OC23CC4CC(CC(C4)C2)C3)c(F)c1
Yield: 171.6 %

Procedure:
A mixture of 16 g (64 mmoles) of 1-adamantanol, 3.35 g (70 mmoles NaH) of 50% NaH in oil, 60 ml of benzene, and 60 ml of dimethylformamide is heated until hydrogen is vigorously evolved (80°). Heating is discontinued until the effervescence subsides, and then the mixture is heated at 90° for 0.5 hour. To this mixture cooled to 20° is added dropwise with stirring 9.7 g (63 mmoles) of 3,4-difluoronitrobenzene. A slight exotherm is observed, and the mixture is refluxed (110° ) for 64 hours. Water (300 ml) is added to the cooled mixture, and it is extracted with CH2Cl2 (200 ml). The CH2Cl2 layer is washed with water (3×300 ml), and the four separate wash water portions are extracted in succession with the same 200 ml of CH2Cl2. The combined organic layers are dried, and concentrated to give 31.5 g of solid crude product, which is chromatographed on silica gel (3100 g), eluting with CH2Cl2, and taking 500 ml fractions. Fractions 14 and 15 contain 12.6 g of white solid product, m.p. 110.1 - 118.2, as confirmed by nmr spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:9][C:10]([CH3:15])([CH3:14])[C:11]([NH:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)=[O:12]
Reactant: Cc1ccnc(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccnc(NC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methyl-pyridin-2-ylamine (30 g, 0.28 mol) was dissolved in DCM (300 mL) and treated with TEA (41 mL) followed by trimethylacetyl chloride (38 mL) via a dropping funnel over 30 min. The mixture was allowed to stir overnight at RT, then poured into a separatory funnel with water (100 mL) and satd. aq. NaHCO3 (75 mL). The organic layer was extracted, washed with satd. aq. NaHCO3 (75 mL), dried over Na2SO4, and concentrated to give solid 2,2-dimethyl-N-(4-methyl-pyridin-2-yl)-propionamide (42 g, 0.22 mol). 1H NMR (CDCl3) δ 8.09 (m, 2 H), 7.93 (br s, 1 H), 6.83 (m, 1 H), 2.33 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@H:10]([CH2:19][CH2:20]O)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](OC(=O)[C@H](CCO)[NH:29][C:30](OC(C)(C)C)=[O:31])C=C.[CH2:41]([O:48][CH2:49][N:50]1[CH:55]=[C:54]([CH3:56])[C:53](=[O:57])[NH:52][C:51]1=[O:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:30]1(=[O:31])[NH:29][C:1](=[O:8])[C:2]2=[CH:3][CH:4]=[CH:5][CH:6]=[C:7]12.[CH2:1]([O:8][C:9](=[O:22])[CH:10]([CH2:19][CH2:20][N:52]1[C:53](=[O:57])[C:54]([CH3:56])=[C:55]([CH3:23])[N:50]([CH2:49][O:48][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:51]1=[O:58])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn(COCc2ccccc2)c(=O)[nH]c1=O
Reactant: C=CCOC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Product: Cc1c(C)n(COCc2ccccc2)c(=O)n(CCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c1=O
Product: O=C1NC(=O)c2ccccc21
Yield: 69 %

Procedure:
In a similar manner to that described in Example 1(1), a reaction was carried out using (±)-N-(tert-butoxycarbonyl)homoserine benzyl ester, instead of (±)-N-(tert-butoxycarbonyl)homoserine allyl ester, and using 1-benzyloxymethyl-5-methyl-pyrimidine-2,4-dione, instead of phthalimide, to afford the desired compound (yield 69%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])[OH:16])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])[OH:16])[CH:10]=2)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1cccc(O)c1
Product: OB(O)c1cccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and 3-hydroxyaniline were reacted to produce 5-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.68 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 1H), 8.10 (d, 1H, J=3.9 Hz), 7.88-7.80 (m, 2H), 7.54 (d, 1H, J=7.2 Hz), 7.31 (t, 1H, J=7.2 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.98-6.93 (m, 2H), 6.35 (d, 1H, J=8.4 Hz); LCMS: purity: 96%; MS (m/e): 341 (MH+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:25]1([O:31][CH2:32][CH2:33][CH2:34][Br:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC#N>[Br-:35].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)([OH:10])[C:4]23[CH2:5][CH2:6][N+:1]([CH2:34][CH2:33][CH2:32][O:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([CH2:2][CH2:3]2)[CH2:8][CH2:7]3)=[CH:12][CH:13]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccccc1
Solvent: CC#N
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C12CC[N+](CCCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 65.4 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl[bis(4-fluorophenyl)]methanol (0.0538 g, 0.163 mmol) and 3-bromopropyl phenyl ether (0.0386 mL, 0.245 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.058 g, 65.2%). EI-MS m/z 464 (M+) Rt (2.16 min).
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CC(C)([O-])C.[Na+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: COc1cccnc1I
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccnc1N1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C

Procedure:
Toluene (1.5 mL) was added to a mixture of 2-iodo-3-methoxypyridine (350 mg, 1.49 mmol), BOC-homopiperazine (0.410 mL, 2.09 mL), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (26 mg, 0.07 mmol), and trisdibenzylideneacetone dipalladium (20 mg, 0.02 mmol). To this suspension was added sodium t-butoxide (201 mg, 2.09 mmol) and the mixture was heated to 65° C. for 15 h. The mixture was filtered through celite, and the filter cake was washed with EtOAc. The resulting solution was washed with H2O, then brine, and dried over MgSO4. After removal of the solvent, the residue was purified on silica to give 335 mg of the title compound as a dark oil. MS (ES) m/z 308 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9](=[O:11])[CH3:10].[CH3:12][O:13][CH2:14][CH2:15][C:16]#[CH:17].C(OCC)C>O1CCCC1>[CH3:12][O:13][CH2:14][CH2:15][C:16]#[C:17][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[O:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Oc1cnccc1I
Reactant: C#CCCOC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCC#Cc1ccncc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.95 mmol Palladium dichloride bis-triphenylphoshine and 0.97 mmol cupric chloride are dissolved in 64 ml tetrahydrofuran under an argon atmosphere. A solution of 30 mmol acetic acid 4-iodo-pyridin-3-yl ester [289473-46-7] and 38 mmol 4-methoxy-but-1-yne [36678-08-7] in 50 ml tetrahydrofuran is added in one portion and the reaction mixture is stirred at room temperature for 1 hour. 300 ml of diethyl ether are added and the precipitate is filtered off. The filtrate is washed successively with saturated, aqueous ammonium chloride solution (3×), water (2×) and brine. The organic layer is dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]#[N:13])=[CH:7][CH:6]=1.[CH3:14][N:15]1[C:19]([C:20]#[N:21])=CC=C1B(O)O.C(=O)([O-])[O-].[K+].[K+].[C:31](P(C(C)(C)C)C(C)(C)C)(C)([CH3:33])[CH3:32].[Br-]>C1COCC1>[C:20]([C:19]1[N:15]([CH3:14])[C:4]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]#[N:13])=[C:7]([CH2:32][CH2:31][CH3:33])[CH:6]=2)=[CH:3][CH:2]=1)#[N:21]
Reactant: N#CNc1ccc(CCCBr)cc1
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1cc(-c2ccc(C#N)n2C)ccc1NC#N
Yield: 375.3 %

Procedure:
4-bromopropylphenylcyanamide (0.125 g, 5 mmol) tris(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol) were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous flow of nitrogen and THF (2 mL) was added with stirring. Tri-tert-butylphosphine (0.0486 mL, 0.0252 mmol) was added to the mixture and allowed to stir until the starting bromide was consumed. The mixture was then diluted with 1/1 hexane/ethylacetate and filtered through a plug of silica gel, solvent was evaporated and the residue was flash chromatographed using 4/1 Hexane/THF to give (0.025 g, 18%) of [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-propylphenyl]cyanamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([OH:26])=[C:21]([Cl:27])[CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:25][C:23]1[CH:24]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:20]=[C:21]([Cl:27])[C:22]=1[OH:26]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cc(Cl)c(O)c(Cl)c3)c2cc1OC

Procedure:
A reaction mixture of 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 213.6 mg (1.2 mmol) of 4-amino-2,6-dichlorophenol and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 1 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether/ethyl acetate (1:1). After drying in vacuo, this yielded 346.7 mg (88.8%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 389.8, 391.8.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.25 g, 1.34 mmol) in dichloromethane (10 mL) was added 3-(trifluoromethyl)benzaldehyde (0.3 g, 1.745 mmol) and sodium triacetoxyborohydride (0.43 g, 2.01 mmol). The mixture was stirred at room temperature for 16 hours. Then the reaction mixture was diluted with dichloromethane and washed with NaHCO3 solution. The organic layer was dried with MgSO4, concentrated, and purified by flash chromatography, eluting with 50% ethyl acetate/hexane to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14]Br)[CH:8]=2)[CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:6]=[CH:5]2
Reactant: C1CCNC1
Reactant: BrCCOc1ccc2cc(Br)ccc2c1
Product: Brc1ccc2cc(OCCN3CCCC3)ccc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
In a flask containing 0.5 g (1.5 mmol) the product from Example 37A, 10 mL of pyrrolidine was added. After stirring at 80° C. for 3 h, the reaction mixture was concentrated under vacuum. The residue was diluted with 100 mL of CH2Cl2 and washed sequentially with water, sodium bicarbonate and brine, dried and evaporated under reduced pressure. Silica gel chromatography (MeOH:CH2Cl2, 95:5) gave the desired material in 98% yield. 1HNMR (300 MHz, CDCl3) δ 1.80 (m, 4H), 2.6 (m, 4H), 2.97 (t, 2H), 4.20 (t, 2H), 2.49 (m, 2H) 7.10–7.90 (m, 6H); MS (ESI) m/z 321 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][NH:9][CH2:10][C:4]=2[CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][N:9]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:10][C:4]=2[CH:3]=1
Reactant: Brc1cnc2c(c1)CNCCN2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N1CCNc2ncc(Br)cc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a solution of 7-bromo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine (432 mg, 1.89 mmol) and TEA (0.28 mL, 2.02 mmol) in anhydrous CH2Cl2 (20 mL) under argon was added methanesulfonyl chloride (0.16 mL, 2.06 mmol). The mixture was stirred for 12 h at room temperature. Mixture was then concentrated to a brown solid and redissolved in a 2:1 MeOH:DMSO mixture. Purification by preparative HPLC (water/acetonitrile/0.05% TFA mixture) gave the title compound (7-bromo-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine) (281 mg, 48%) as a yellow solid: 1H NMR (200 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.68 (s, 1H), 4.39 (s, 2H), 3.48 (s, 2H), 3.39 (s, 2H), 2.79 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH:15](Br)C.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.C(Cl)(Cl)Cl>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CC(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
A solution of N-(4-hydroxyphenyl)acetamide (paracetamol) (1) (1.50 g) and 1,3-dibromobutane (14) (10.0 ml) in ethyl methyl ketone (25.0 ml) containing potassium carbonate (5.0 g) was stirred overnight at room temperature. The reaction mixture was filtered, residue washed with ethyl methyl ketone and solvent evaporated under reduced pressure to get the residue. The residue was dissolved in chloroform (200.0 ml), washed with 5% NaOH solution (3×100 ml), water (3×50 ml), dried, filtered and crystallized from methanol to get the desired product N-[4-(3-Bromo-propoxy)-phenyl]-acetamide (16) (2.01 g, 75.8%), mp 115-118° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][CH:20]=[CH:21][CH2:22][CH2:23]Br>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:23][CH:22]=[CH:21][CH2:20][Br:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(O)ccc21
Reactant: BrC=CCCBr
Product: CC(C)(C)OC(=O)N1CCCc2cc(OCC=CCBr)ccc21

Procedure:
In analogy to example 2.2, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and 1,4-dibromobutene were converted to yield 6-(4-Bromo-but-2-enyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless oil, MS: 381 (M, 1Br);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:14][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(OC)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(OC)c1
Reaction time: 2 h

Procedure:
A mixture of 15.7 g (87.1 mmol) of methyl (3-methoxyphenyl)acetate, 16.3 g (91.5 mmol) of N-bromosuccinimide and a catalytic amount of AIBN in tetrachloromethane (150 ml) was heated under reflux with stirring for 2 h. The cooled reaction solution was filtered and the solvent was removed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:20][C:21]1[CH:43]=[CH:42][C:24]([C:25]([N:27]2[CH2:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[CH2:30][C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]2=3)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:38]1[C:29]2[CH2:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[CH2:33][N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:4](=[O:5])[C:3]4[CH:7]=[C:8]([Cl:12])[CH:9]=[C:10]([Cl:11])[C:2]=4[Cl:1])=[CH:43][CH:42]=3)=[O:26])[C:28]=2[CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)cc(Cl)c1Cl
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
A mixture of 366 mg of 2,3,5-trichlorobenzoyl chloride and 151 mg of triethylamine in 2 ml of methylene chloride is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. Stirring is continued for 1.5 hours. The reaction mixture is partitioned with water and the organic layer is washed with 1N HCl water, 0.5 N NaOH and brine. The organic layer is dried with Na2 SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.52 g of white solid residue which is purified by column chromatography on silica gel by elution with 2:1 hexane-ethyl acetate to give 120 mg of the desired product as a crystalline solid, m.p. 225°-230° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[NH:22][C:21](=[O:27])[CH:20]=[C:19]2[CH3:28])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[O-][CH2:32]C.[Tl+].CI.CO>CN(C)C=O>[F:30][C:2]([F:1])([F:29])[C:3]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[N:22]([CH3:32])[C:21](=[O:27])[CH:20]=[C:19]2[CH3:28])([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: CC[O-]
Reactant: Cc1cc(=O)[nH]c2c(C)cc(C(OCc3ccccc3)(C(F)(F)F)C(F)(F)F)cc12
Agent: [Tl+]
Solvent: CI
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(C)c2c(C)cc(C(OCc3ccccc3)(C(F)(F)F)C(F)(F)F)cc12

Procedure:
To a solution of 6-[2,2,2-trifluoro-1-benzyloxy-1-(trifluoromethyl)ethyl]-4,8-dimethyl-2(1H)-quinolinone in dimethylformamide is added an equivalent of thallium ethoxide. The solution is stirred under nitrogen. To the solution is added methyl iodide, and the solution is stirred and heated to 50° until thin layer chromatography indicates the reaction is complete. The solution is cooled and treated with 5 ml of methanol. The cooled solution is filtered and evaporated at reduced pressure. The residual material is extracted with hexane and the filtered solution is evaporated at reduced pressure. The residual material is heated to 250° in a nitrogen atmosphere for 4 hours. At the end of this period, the residual material is chromatographed on silicic acid to give 6-[2,2,2-trifluoro-1-benzyloxy-1-(trifluoromethyl)ethyl]-1,4,8-trimethyl-2(1H)-quinolinone.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of 6-phenyl-1-hexanol (2.9 g, 16.27 mmoles), CH2Cl2 (30 ml), triethylamine (4.76 ml, 34.16 mmoles) and p-toluensulphonyl chloride (3.26 g, 17.08 mmoles) was kept under stirring at room temperature for 1 night, washed with water, 5% HCl and NaHCO3 and evaporated to give 5.4 g of the title compound (yield: 100%).
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.[CH3:33]CN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CO>[CH3:33][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([C:14](=[O:15])/[CH:13]=[CH:12]/[C:10]2[CH:11]=[C:6]([C:5]3[S:1][C:2]4[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=4[CH:4]=3)[C:7]([O:27][CH3:28])=[CH:8][C:9]=2[O:25][CH3:26])=[CH:17][CH:18]=1
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4s3)c(OC)cc2OC)cc1
Yield: 34 %

Procedure:
The title compound was prepared by esterification of 4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid (Ex-3) with methanol in the presence of EDCI and DMAP. Yellow solid, 34% yield, m.p. 149–151° C. 1H-NMR (300 MHz, CDCl3): 8.17 (d, 2H, J=6.7 Hz), 8.10 (d, 1H, J=15.8 Hz), 8.05 (d, 2H, J=6.7 Hz), 7.95 (s, 1H), 7.82 (m, 2H), 7.67 (s, 1H), 7.57 (d, 1H, J=15.8 Hz), 7.33 (m, 2H), 6.58 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 3.97 (s, 3H). MS m/z=458 ([M]+, 100%). HRMS (EI) Calcd. for C27H22O5S: 458.118 Found: 458.1196.