Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][B:2]1[C@@H:7]([NH:8][C:9](=[O:16])[CH2:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][C@@H:4]([CH2:17][C:18]([OH:20])=[O:19])[O:3]1.Cl.[CH3:22][CH2:23]OC(C)=O.CCOCC>C(O)C>[OH:1][B:2]1[C@@H:7]([NH:8][C:9](=[O:16])[CH2:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][C@@H:4]([CH2:17][C:18]([O:20][CH2:22][CH3:23])=[O:19])[O:3]1
Reactant: O=C(O)C[C@@H]1CC[C@H](NC(=O)Cc2cccs2)B(O)O1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1CC[C@H](NC(=O)Cc2cccs2)B(O)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
To a solution of 5 (400 mg, 1.35 mmol) in 4 mL of absolute ethanol was added anhydrous 1M HCl in EtOAc (4 mL, 4 mmol). The reaction was stirred at room temperature for 16 h. The mixture was then concentrated and azeotroped with acetonitrile (3×10 mL) to give a sticky solid. Ether (10 mL) was added to the azeotroped sticky solid and the resulting precipitate was filtered. The filtered solid was rinsed with additional ether (5 mL) and dried to give ethyl 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetate 65 (300 mg, 0.92 mmol, 68.5% yield). 1H NMR (CD3OD) δ ppm 0.98-1.09 (q, J=14 Hz, 1H), 1.23-1.26 (t, J=7 Hz, 3H), 1.49-1.54 (dd, J=14 Hz, J=3 Hz, 1H), 1.57-1.64 (dt, J=11 Hz, J=2 Hz, 1H), 1.72-1.78 (brd, J=14 Hz, 1H), 2.24-2.28 (dd, J=15 Hz, J=6 Hz, 1H), 2.34-2.39 (dd, J=15 Hz, J=8 Hz, 1H), 2.63 (brs, 1H), 3.99 (s, 2H), 4.07-4.13 (q, J=4 Hz, 3H), 6.99-7.01 (t, J=4 Hz, 1H), 7.05-7.06 (d, J=3 Hz, 1H), 7.35-7.36 (dd, J=5 Hz, J=1.3 Hz, 1H); ESIMS found for C14H20BNO5S m/z 308.1 (M−H2O)+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:18]#N)=[CH:13][CH:12]=1.C([O:27]CC)C>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:27])=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOCC
Reactant: COc1ccc(C(C#N)O[Si](C)(C)C)cc1
Product: COc1ccc(C(O[Si](C)(C)C)C(=O)c2ccccc2)cc1
Reaction time: 2 h
Yield: 85 %

Procedure:
To a diluted solution of 3.0 M phenylmagnesium bromide (Aldrich, 39 mL, 0.12 mol) in anhydrous diethyl ether (500 mL) was slowly added a solution of (4-methoxyphenyl)-trimethylsilanyloxy-acetonitrile (36.13 g, 0.11 mol), which obtained in Step 1, in anhydrous diethyl ether (50 mL) at 4° C. After addition was complete, the reaction solution was elevated to room temperature and stirred for 2 hours. The reaction was quenched by slow addition of 3N HCl solution (200 ml). After separation of an organic layer and aqueous layer, the thus-obtained organic layer was washed twice with 100 mL of a saturated sodium bicarbonate solution and then successively washed twice with 100 mL of a brine solution. The organic layer obtained was dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give 30.54 g (yield: 85%) of 2-(4-methoxyphenyl)-1-phenyl-2-trimethylsilanyloxy-ethanone as a desired product.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:6]=1I.[CH2:19]([Li])CCC.IC>C1COCC1>[I:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:6]=1[CH3:19]
Reactant: [Li]CCCC
Reactant: Cc1nc(I)c(I)n1-c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nc(I)c(C)n1-c1ccc(C(F)(F)F)cc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
4,5-Diiodo-2-methyl-1-(4-trifluoromethyl-phenyl)-1H-imidazole (1.0 g, 2.1 mmol) was dissolved in 15 ml THF and cooled to −75° C. n-Butyllithium (1.6M in Hexane) (1.60 ml, 2.5 mmol) was added, and the mixture stirred for 60 min at −75° C. Iodomethane (0.19 ml, 3.0 mmol) was added and stirring was continued 30 min. at −75° C. and then 1 h without dry ice bath. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 100:0→60:40 gradient) and by recrystallization from little ethyl acetate and cyclohexane. The desired compound was obtained as a white solid (197 mg, 26%), MS: m/e=367.0 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]([NH:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)c1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 5 (250 mg, 1.42 mmol) in N,N-dimethylformamide (4 mL) was added 1,3-diisopropylcarbodiimide (0.268 mL, 1.70 mmol), 1-hydroxybenzotriazole hydrate (58 mg, 0.4 mmol), and t-butyl glycinate (223 mg, 1.7 mmol). The mixture was stirred at room temperature overnight, quenched with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (50:1) as the mobile phase to provide the desired product. MS (APCI): m/z 290 (M+H)+.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate. Yield: 62% of theory, C30H32N6O5 (556.6) Rf value: 0.51 (silica gel; dichloromethane/ethanol=19:1) ##EQU63##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[O:15])[CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[CH:25]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[O:15])[CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1cccnc1)c1cccnc1
Reactant: O=c1ccccn1Cc1cccc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ccccn1C(c1cccc(Cl)n1)C(c1cccnc1)c1cccnc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To the solution of 1-[(6-chloropyridin-2-yl)methyl]pyridin-2(1H)-one (0.3 g, 1.36 mmol) in THF (6 mL) at −78° C. was added LDA(0.83 mL, 1.8 M) and stirred at −78° C. for 1 h. The solution of 3-[chloro(pyridin-3-yl)methyl]pyridine (0.278 g, 1.36 mmol) in THF (3 mL) was added and the mixture was warmed to 0° C. and stirred at 0° C. for 1 h. The reaction was quenched with water and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give (±)-1-[1-(6-chloropyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one. 1H-NMR (500 MHz, CDCl3) δ 8.58 (d, 1H, J=2.2), 8.53 (d, 1H, J=2.0), 8.42 (dd, 1H, J=4.6, 1.2), 8.35 (dd, 1H, J=4.6, 1.2), 7.92 (d, 1H, 3=6.6), 7.84 (d, 1H, J=8.0), 7.64 (d, 1H, J=8.0), 7.48 (t, 1H, J=7.7), 7.25-7.09 (m, 6H), 6.41 (d, 1H, J=9.0), 6.09 (t, 1H, J=6.7), 5.30 (d, 1H, J=12.2). LRMS m/z (M+H) Calcd: 389.8. found: 389.0.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CO)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 5.20 (2H, s), 5.74 (1H, s, J=1.6 Hz), 7.19-7.32 (4H, m), 7.38 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.56 (1H, s, J=1.2 Hz), 8.02 (1H, s), 8.70 (1H, s, J=4.8 Hz). [M+H] Calc'd for C17H14N4O, 291; Found, 291.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7](N2CCN(C)CC2)[C:6]([N+:16]([O-])=O)=[CH:5][C:4]=1[NH:19][C:20]1[N:25]=[C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)[CH:23]=[CH:22][N:21]=1.[NH4+:36].[Cl-].[CH2:38]([OH:40])C>O.[Fe]>[CH3:38][O:40][C:7]1[CH:8]=[C:3]([N:36]2[CH2:30][CH2:29][N:28]([CH3:35])[CH2:27][CH2:26]2)[C:4]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[CH:5][C:6]=1[NH2:16]
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CCO
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: COc1cc(N2CCN(C)CC2)c(Nc2nccc(-c3cn(C)c4ccccc34)n2)cc1N
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methy-lindol-3-yl)pyrimidin-2-amine (Intermediate 111, 329 mg, 0.69 mmol), iron (233 mg, 4.17 mmol) and NH4Cl (26.0 mg, 0.49 mmol) in ethanol (12 mL) and water (4 mL) were heated at reflux for 3 h. The mixture was allowed to cool to r.t. and then filtered. The filtrate was concentrated in vacuo. Purification by ion exchange chromatography, using an SCX column and eluting with 0.7M methanolic ammonia gave a brown gum after concentration of appropriate fractions in vacuo. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (287 mg, 93%) as a light brown gum; 1H NMR: (CDCl3) 2.37 (3H, br s), 2.59 (4H, s), 2.92-2.99 (4H, m), 3.79-3.86 (5H, m), 3.87 (3H, s), 6.71 (1H, s), 7.01 (1H, d), 7.27-7.34 (2H, m), 7.35-7.40 (1H, m), 7.57 (1H, s), 7.78 (1H, s), 8.17 (1H, s), 8.32 (1H, d), 8.47-8.53 (1H, m); m/z: ES+ MH+ 444.54.
Reaction SMILES: [C:1]12([S:11][CH2:12][CH2:13][NH2:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O-].[Na+].Br[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21]>C(O)(C)(C)C>[C:23]([CH:19]([C:20]([OH:22])=[O:21])[NH:14][CH2:13][CH2:12][S:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(Br)C(=O)O
Reactant: NCCSC12CC3CC(CC(C3)C1)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)C(NCCSC12CC3CC(CC(C3)C1)C2)C(=O)O

Procedure:
A mixture of 42.3 parts of 2-(1-adamantylthio)ethylamine, 10.8 parts of sodium methoxide, 39.0 parts of 2-bromo-2-tert-butyl acetic acid and 315 parts of tert-butanol is refluxed, under a nitrogen atmosphere, for 5 hours. The product is recovered in the manner described in Example 5 to yield 2-tert-butyl-N-[2-(1 -adamantylthio)ethyl-]glycine, melting at about 220°-230°.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: COc1ccccc1Br
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromoanisole
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21]1[C:29]([Br:30])=[CH:28][C:24]([C:25](Cl)=[O:26])=[C:23](C)[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl.O>[CH2:13]([O:20][C:21]1[C:29]([Br:30])=[CH:28][C:24]([C:25]([N:3]([O:4][CH3:5])[CH3:2])=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNOC
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C

Procedure:
To a suspension of 4-(benzyloxy)-5-bromo-2-methylbenzoic acid (16.6 g, 51.7 mmol) in chloroform (80 mL) were added oxalyl chloride (5 mL, 56.9 mmol) and N,N-dimethylformamide (6 drops), and the mixture was stirred for an hour at room temperature. And then the reaction solution was concentrated to obtain 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride. Then to a chloroform suspension (60 mL) of N,O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) cooled in ice was added dropwise a chloroform solution (60 mL) of 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride, and the mixture was stirred for an hour at room temperature. To the reaction solution cooled in ice were added water and chloroform to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide. To a tetrahydrofuran solution (150 mL) of the 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide was added at −10° C. lithium aluminum hydride (1.96 g, 51.7 mmol), and the mixture was stirred for an hour at the same temperature. To the reaction solution were added 1 M hydrochloric acid, and then ethyl acetate to separate an organic layer. The organic layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde. To a toluene solution (120 mL) of the 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde were added ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol), and heated to reflux for 1.5 hours with a Dean-Stark apparatus. To the reaction solution was added ethyl acetate to separate an organic layer. The organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1). In addition, the residue was further purified with NH type silica gel column chromatography (chloroform) to obtain the title compound (12.8 g, 71%, 3 steps) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[CH3:28][CH:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)[CH3:30].[OH-].[Na+]>CS(C)=O.O>[ClH:1].[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:44][C:41]4[CH:42]=[CH:43][C:38]([O:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][CH:29]([CH3:28])[CH3:30])=[CH:39][CH:40]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Reactant: CC(C)NCCCCCOc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)NCCCCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Product: Cl
Reaction time: 5 h
Yield: 145.4 %

Procedure:
A solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (9.2 g) and 4-[5-(1-methylethyl)aminopentoxy]phenol (5.16 g) in 150 ml dimethylsulfoxide was treated with sodium hydroxide (0.87 g) in water (7 ml) and was stirred at 55°-60° for 5 hours. The usual work-up furnished the crude trihydrochloride salt which was recrystallized from methanol to give 5.8 g of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-[2-[4-[5-(1-methylethyl)aminopentoxy]phenoxy]ethyl]piperazine trihydrochloride, mp 237°-239°.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:5][CH:4]=[C:3]1[C:21]([OH:23])=[O:22].C(Cl)(=O)C(Cl)=O.[C:30]1(=O)[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH2:31]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C=O>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:5][CH:4]=[C:3]1[C:21]([O:23][C:30]1[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH:31]=1)=[O:22]
Reactant: O=C1CCCC(=O)C1
Reactant: O=C(O)c1cnc(-c2ccccc2)n(Cc2ccccc2)c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C=C(OC(=O)c2cnc(-c3ccccc3)n(Cc3ccccc3)c2=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,6-dihydro-6-oxo-2-phenyl-1-(phenylmethyl)-5-pyrimidinecarboxylic acid (i.e. the product from Step C) (1.00 g, 3.26 mmol) in dichloromethane (30 mL) at 0° C., was added oxalyl chloride (823 mg, 6.53 mmol) followed by a catalytic amount of N,N-dimethylformamide (2 drops). The reaction mixture was allowed to warm to room temperature and stir for 1 h. Then the reaction mixture was concentrated under reduced pressure. To the resulting residue was added dichloromethane (30 mL) and 1,3-cyclohexanedione (440 mg, 3.90 mmol), followed by triethylamine (990 mg, 9.80 mmol), and the reaction mixture was stirred at room temperature for 30 min Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford the title product as a white solid (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=S)=[CH:4][CH:3]=1.[N:21]#[C:22][NH2:23].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:23][C:22]#[N:21])=[N:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: S=C(NCCOc1ccc(Cl)cc1)Nc1cccnc1
Reactant: N#CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#CNC(=Nc1cccnc1)NCCOc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
N-(2-p-Chlorophenoxyethyl)-N'-3-pyridylthiourea (1.05 g) was suspended in acetonitrile (10 ml), and cyanamide (285 mg), N,N'-dicyclohexylcarbodiimide (1.40 g) and triethylamine (0.04 ml) were added. The mixture was kept with stirring at room temperature for a week, when it was filtered, washed with acetonitrile and with ether. The solid mixture of the crude product and N,N'-dicyclohexylthiourea was extracted with chloroform (15 ml) to leave the pure product, which was collected by filtration and washed with chloroform and ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].[CH2:11]1[O:13][CH2:12]1.C1OC1C>[Cl-].C[N+](C)(C)C>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH:12]([OH:13])[CH3:11]
Reactant: C1CO1
Reactant: Oc1c(Br)cc(Br)cc1Br
Agent: CC1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: CC(O)Oc1c(Br)cc(Br)cc1Br

Procedure:
Monomers of type (e) are prepared by the reaction of 2,4,6--tribromophenol with an alphaolefin oxide such as ethylene oxide and propylene oxide, in the presence of 1 to 3 percent tetramethylammonium chloride at 80° to 100°C. for 3 to 6 hours to form 2,4,6-tribromophenoxyethanol. The reaction mixture is washed thoroughly with water after dissolving in solvent, dried with a drying agent, and stripped of solvent under reduced pressure at 40° to 60°C. The product is then analyzed for hydroxyl number. The yield of this intermediate is generally 40 to 60%. The intermediate is then reacted with maleic anhydride at 80° to 100°C. for 3 to 5 hours to form mono-2,4,6-tribromophenoxyethyl maleate.
Reaction SMILES: FCCC[O:5][C:6]1[CH:14]=[C:13]2C(CC3(CCC(=O)CC3)C2=O)=[CH:8][CH:7]=1.[F:22][C:23]([F:38])([F:37])[CH2:24][CH2:25][O:26][C:27]1[CH:35]=[C:34]2[C:30]([CH2:31][CH2:32][C:33]2=[O:36])=[CH:29][CH:28]=1.C(OC)(=O)C=C>>[F:22][C:23]([F:37])([F:38])[CH2:24][CH2:25][O:26][C:27]1[CH:35]=[C:34]2[C:30]([CH2:31][C:32]3([CH2:13][CH2:14][C:6](=[O:5])[CH2:7][CH2:8]3)[C:33]2=[O:36])=[CH:29][CH:28]=1
Reactant: O=C1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=O
Reactant: O=C1CCc2ccc(OCCC(F)(F)F)cc21
Solvent: C=CC(=O)OC
Product: O=C1CCC2(CC1)Cc1ccc(OCCC(F)(F)F)cc1C2=O
Yield: 58 %

Procedure:
The title compound (854 mg, 58% yield) was prepared using the method described for Intermediate 63 starting from 6-(3,3,3-trifluoropropoxy)-2,3-dihydro-1H-inden-1-one (Intermediate 47, 1.08 g, 4.42 mmol) and methyl acrylate (878 μL, 9.73 mmol): 1H NMR (500 MHz, CDCl3) δ ppm 1.82-1.92 (m, 2 H), 2.17-2.27 (m, 2 H), 2.42-2.53 (m, 2 H), 2.60-2.75 (m, 4 H), 3.14-3.20 (m, 2 H), 4.22-4.27 (m, 2 H), 7.19-7.22 (m, 1 H), 7.25 (dd, 1 H), 7.41 (d, 1 H): MS (ES+) m/z 327 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C1COCC1.CCOC(C)=O>[Br:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: NCCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCCNc1cccc(Br)n1

Procedure:
A solution of 2,6-dibromopyridine (10 g, 42 mmol) and 3-aminopropanol (3.5 mL, 46 mmol) in THF (60 mL) was stirred at reflux for 48 h. The reaction mixture was diluted with EtOAc and washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give 3-(6-bromo-pyridin-2-ylamino)-propan-1-ol as a light-yellow oil which crystallized on standing at RT to a white solid. MS m/z: 232.0 (M+H). Calc'd for C8H11BrN2O 231.09.
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([C:20]([CH3:23])([CH3:22])[CH3:21])[O:3][C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[C:12](=[O:13])[C:6]=2[CH:5]=1.[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[CH3:1][Si:2]([CH3:24])([C:20]([CH3:22])([CH3:21])[CH3:23])[O:3][C:4]1[CH:19]=[CH:18][C:7]2[O:8][CH2:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[CH:12]([OH:13])[C:6]=2[CH:5]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(O)c1ccccc1CO2
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A solution of 5 g of 2-(dimethyl-t-butylsilyloxy)-6,11-dihydrodibenz[b,e]oxepin-11-one in 50 ml of methanol is cooled to 0° C. After adding 2 g of sodium borohydride and the mixture is stirred for 1 hour, 300 ml of chloroform is added and the mixture is washed with water and a saturated saline solution, followed by drying over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to silica-gel chromatography and eluted with toluene to give 4.1 g of 2-(dimethyl-t-butylsilyloxy)-6,11-dihydrodibenz[b,e]oxepin-11-ol (oil). Mass spectrum m/z: 342(M+).