Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:25])[CH:16]2[Si:21](Cl)([CH3:23])[CH3:22].O>CCOCC>[Br:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:25])[CH:16]2[Si:21]([CH:4]1[CH:3]=[CH:2][CH:1]=[CH:5]1)([CH3:23])[CH3:22]
Reactant: C1=CCC=C1
Reactant: CC1=Cc2c(Br)cccc2C1[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC1=Cc2c(Br)cccc2C1[Si](C)(C)C1C=CC=C1
Temperature: 0 °C

Procedure:
To a solution of 1.32 g (20.0 mmol) of freshly distilled cyclopentadiene in 120 ml of ether, 8.00 ml of 2.5 M (20.0 mmol) nBuLi in hexanes was added dropwise, while vigorously stirring, at 0° C. This mixture was stirred for 2 h at room temperature, and then 6.03 g (20.0 mmol) of (4-bromo-2-methyl-1H-inden-1-yl)(chloro)dimethylsilane was added dropwise over 30 min at −80° C. The resulting mixture was stirred for 1 h at this temperature, for 12 h at room temperature, and then 100 ml of water was added. The organic layer was separated. The aqueous layer was extracted with 2×100 ml of dichlorodimethylsilane. The combined organic fractions were dried over Na2SO4 and evaporated to dryness. The product was isolated using flash-chromatography on Silica Gel 60 (40-63 um, d 30 mm, 1 300 mm, eluent: hexanes). Yield 5.50 g (83%) of colorless oil of a mixture of isomers I, II, and III.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[NH:5][C:3]1=[O:4].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[N:5]([CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15])[C:3]1=[O:4]
Reactant: Cn1c(=O)[nH]c2ncn(C)c2c1=O
Reactant: C=CCCCCBr
Product: C=CCCCCn1c(=O)n(C)c(=O)c2c1ncn2C

Procedure:
is prepared analogously to Example 6 from 1,7-dimethyl-xanthine and 6-bromo-hex-1-ene.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:24][O:25]C1CCCCO1)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([NH:21][CH:22]=O)[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.B#B.O.Cl>O1CCCC1>[NH2:8][CH:9]([CH2:24][OH:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([NH:21][CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(COc1noc2ccc(NC=O)cc12)COC1CCCCO1
Agent: B#B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc2onc(OCC(N)CO)c2c1

Procedure:
3-[2-tert-Butoxycarbonylamino-3-(2,3,4,5-tetrahydropyranyloxy)propoxy]-5-formylamino-1,2-benzoisoxazole is dissolved in 9 ml of tetrahydrofuran, and at 5°-10° C., 3.2 ml of a tetrahydrofuran solution (1M) of diborane is added, after which they are subjected to reaction at 20°-25° C. for one hour. Subsequently, 9 ml of water is added and the pH is adjusted to 0 with 6N hydrochloric acid, after which they are subjected to reaction at 20°-25° C. for one hour. The reaction mixture is concentrated under reduced pressure, ethyl acetate is added, and, after shaking, the aqueous layer is separated. Ethyl acetate is added again to the separated aqueous layer and the pH is adjusted to 11 with potassium carbonate, after which the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure, to obtain 0.22 g of brown, oily 3-(2-amino-3-hydroxypropoxy)-5-methylamino-1,2-benzoisoxazole.
Reaction SMILES: C([BH3-])#N.[Na+].[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:15])[NH:10]2.O>C(O)(=O)C>[OH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([CH3:15])[NH:10]2
Reactant: Cc1cc2c(O)cccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1Cc2c(O)cccc2N1
Temperature: 14 °C
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
1.35 g of sodium cyanoborohydride are gradually added to a solution of 1 g of 4-hydroxy-2-methylindole in 35 ml of acetic acid under argon cooled to a temperature of about 14° C. The reaction mixture is stirred at a temperature of about 14° C. for 15 minutes, and is then allowed to warm up to ambient temperature. After 1.5 hours, the reaction mixture is treated with 15 ml of water, stirred at ambient temperature for 1 hour, and then concentrated to dryness under reduced pressure. The residue is taken up in 75 ml of ethyl acetate and then treated with 60 ml of a saturated sodium hydrogen carbonate solution. After stirring for 1 hour and then settling out, the organic phase is separated and the aqueous phase is extracted with 50 ml of ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 70 g cartridge of 15-40 μm silica, elution being carried out with an 80/20 v/v cyclohexane/ethyl acetate mixture, with a flow rate of 80 ml/min. 0.87 g of 4-hydroxy-2-methylindoline is thus obtained in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:2].[N+:15]([O-])([OH:17])=[O:16].O.N>S(=O)(=O)(O)O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH3:2]
Reactant: CCOCc1cc2ccccc2cn1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOCc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Ethoxymethylisoquinoline (31 g) is dissolved in 95% sulphuric acid (density 1.83; 100 cc). The solution is cooled to 0° C. and a mixture of 95% sulphuric acid (density 1.83; 35 cc) and 70% nitric acid (density 1.42; 10.2 cc) is added dropwise in the course of 30 minutes so as not to exceed 10° C. Stirring is continued for 16 hours, whilst allowing the temperature to return to about 20° C. The mixture is then poured into a mixture of ice and water (1 liter), and an ammonia solution containing 20% of NH3 (density 0.9) is added, without exceeding 30° C., until a pH of about 10 is obtained. The yellow suspension is extracted with methylene chloride (4×200 cc). The organic extracts are combined, washed with water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). 3-Ethoxymethyl-5-nitroisoquinoline (24 g), melting at 54° C., is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O.[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:14][C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(C(=O)Nc2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 817.5 %

Procedure:
4-Acetylbenzoic acid (4.00 g, 24.4 mmol), 5-aminotetrazole monohydrate (3.00 g, 2.91 mmol) and ethyl dimethylaminopropyl carbodiimide hydrochloride (7.00 g, 3.55 mmol) were dissolved in DMF (25 mL) and stirred at ambient temperature for 48 hours. The reaction mixture was poured into ice-water, and the precipitate collected by filtration to afford 5.50 g (98%) of pure 4-acetyl-N-(2H-tetrazol-5-yl)benzamide after drying overnight in a vacuum oven.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:19][N:20]1[C:28]2[C:23](=[C:24]([NH2:29])[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.[N:30]1([C:36]2[N:37]=[C:38]([CH2:43][C:44]([O-])=[O:45])[NH:39][C:40](=[O:42])[CH:41]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[Na+]>CN(C)C=O>[CH3:19][N:20]1[C:28]2[C:23](=[C:24]([NH:29][C:44](=[O:45])[CH2:43][C:38]3[NH:39][C:40](=[O:42])[CH:41]=[C:36]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:37]=3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cn1ccc2c(N)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1ccc2c(NC(=O)Cc3nc(N4CCOCC4)cc(=O)[nH]3)cccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.6 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 272 mg of 1-methyl-1H-indol-4-ylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 280 mg of N-(1-methyl-1H-indol-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:31])[CH2:9][NH:10][C:11](=[O:30])[CH2:12][NH:13][C:14](=[O:29])[C@@H:15]([NH:17][C:18](=[O:28])[CH2:19][NH:20][C:21]2[S:22][C:23]([CH:26]=[O:27])=[CH:24][N:25]=2)[CH3:16])[C@@H:3]1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.[BH4-].[Na+]>CCO.O>[OH:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:31])[CH2:9][NH:10][C:11](=[O:30])[CH2:12][NH:13][C:14](=[O:29])[C@@H:15]([NH:17][C:18](=[O:28])[CH2:19][NH:20][C:21]2[S:22][C:23]([CH2:26][OH:27])=[CH:24][N:25]=2)[CH3:16])[C@@H:3]1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1
Reactant: COc1ccc(C[C@@H]2[C@H](O)[C@@H](O)CN2C(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)CNc2ncc(C=O)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C[C@@H]2[C@H](O)[C@@H](O)CN2C(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)CNc2ncc(CO)s2)cc1

Procedure:
Following the procedure as described ion Example 32, except using material from Example 44 (21.4 mg, 0.031 mmol), EtOH/H2O (4:1) (2.0 mL) and sodium borohydride (7.2 mg, 0.190 mmol), the title compound is isolated (quantitative yield) and is used crude, “as is”, in the macrocyclization step. LC/MS (Condition A): ret. T=1.90 min, (M+Na) 601.29.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)[CH2:3][CH2:2]1.[Cl:29][C:30]1C=CC(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC4OCCC=4C=3)=N2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:2]=[CH:3][C:1]([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:8][C:7]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[N:6]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(Cl)cc2)c1=O
Reactant: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Product: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(Cc3ccc(Cl)cc3)c2=O)CC1

Procedure:
The general procedure of Example 1 (6) was carried out by use of 2-(4-chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one, to thereby yield the title compound as faint yellow needle-like crystal (yield: 46.3%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])=[CH:2][CH3:3].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Cl)[CH:14]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]=[CH:2][CH3:3])[CH:14]=1)=[CH:2][CH3:3]
Reactant: ClCc1cccc(CCl)c1
Reactant: CC=Cc1ccccc1O
Product: CC=Cc1ccccc1OCc1cccc(COc2ccccc2C=CC)c1

Procedure:
α,α'-bis-(2-propenylphenoxy)-meta-xylene is prepared in a process similar to Example I, except that 383 grams (2.86 mole) of propenylphenol is employed along with 250 grams (1.43 moles) of α,α'-dichloro-meta-xylene to give a reaction product extracted with methylene chloride, washed with potassium hydroxide and dried over magnesium sulfate, then vacuum distilled at 80° C. to yield 407 grams of a viscous liquid (80% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a solution of 1-[(3SR,4RS) 1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone (IX-1) (14.90 g, 0.043 mol) in THF (300 mL) at 0° C. were added portionwise LiAlH4 (2.05 g 0.051 mol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (SR)-1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (XIII-B-1) 4.69 g (31%) as a white solid ES-MS m/e: 350.2 (M+H+) and (RS)-1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (XIII-A-1) 5.30 g (35%) as a white solid ES-MS m/e: 350.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:23]1[CH2:24][CH:25]=[C:26]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:28]1
Reactant: Cc1cccnc1Nc1ccc(Oc2ncccc2Br)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccnc1Nc1ccc(Oc2ncccc2C2=CCOCC2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-3-methylpyridin-2-amine (0.2898 g, 0.814 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.214 g, 1.017 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.046 g, 0.065 mmol), and sodium carbonate (0.431 g, 4.07 mmol) in DME (1.302 mL) and water (0.325 mL) to stir at 80° C. overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-3-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 360.0. IC50 (uM) 0.00701.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:6]=1[F:13])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Br:12][C:8]1[C:9]([F:11])=[CH:10][C:5]([CH2:4][NH2:1])=[C:6]([F:13])[CH:7]=1
Reactant: [N-]=[N+]=NCc1cc(F)c(Br)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(F)c(Br)cc1F
Temperature: 55 °C

Procedure:
To a mixture of the crude azide (110 mg, 0.44 mmol) in THF (3 mL) were added polymer-supported Ph3P (3.0 eq.) and water (1.5 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.40 min; [M+CH3CN+H]+=263.14.
Reaction SMILES: O[CH2:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:27]>C(Cl)Cl>[Br:27][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)c1ccc(C=NOCCCOc2ccc(CO)cc2)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C=NOCCCOc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-formyl-phenoxy)-propyl]-oxime (1.303 g, 3.84 mmol) in methanol (30 mL) was added sodium borohydride (0.201 g, 5.31 mmol) and the reaction was allowed to stir for 20 minutes. It was then poured slowly into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4-tert-butyl-benzaldehyde O-[3-(4-hydroxymethyl-phenoxy)-propyl]-oxime which was used without further purification. To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-hydroxymethyl-phenoxy)-propyl]-oxime in methylene chloride (30 mL) was added phosphorus tribromide (0.400 mL, 4.25 mmol) and the reaction was stirred at room temperature for 30 minutes. It was then poured slowly over ice and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4-tert-butyl-benzaldehyde O-[3-(4-bromomethyl-phenoxy)-propyl]-oxime (˜0.8 g) which was used without further purification. To a solution of 4-tert-butyl-benzaldehyde O-[3-(4-bromomethyl-phenoxy)-propyl]-oxime (−0.8 g) in tetrahydrofuran (25 mL) was added tetrabutylammonium cyanide (0.650 g, 2.42 mmol) and the reaction was allowed to stir at room temperature overnight. It was then poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (10/90 to 15/85) to give {4-[3-(4-tert-butyl-benzylideneaminooxy)-propoxy]-phenyl}-acetonitrile (0.607 g, 45% over 3 steps) as a colorless oil. 1H NMR (300 MHz, CDCl3); δ 8.08 (s, 1H), 7.52 (d, 2H), 7.40 (d, 2H), 7.22 (d, 2H), 6.92 (d, 2H), 4.35 (t, 2H), 4.10 (t, 2H), 3.68 (s, 2H), 2.21 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[F:18][C:19]1[C:24](C2C([N+]([O-])=O)=CC(C#N)=CC=2[N+]([O-])=O)=[CH:23][C:22]([CH3:39])=[CH:21][N:20]=1>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:24]2[C:19]([F:18])=[N:20][CH:21]=[C:22]([CH3:39])[CH:23]=2)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: Cc1cnc(F)c(-c2c([N+](=O)[O-])cc(C#N)cc2[N+](=O)[O-])c1
Product: COC(=O)c1cc([N+](=O)[O-])c(-c2cc(C)cnc2F)c([N+](=O)[O-])c1
Yield: 94 %

Procedure:
The title compound was prepared from 4-chloro-3,5-dinitro-benzoic acid methyl ester in 94% yield according to the procedure outline for the preparation of Compound 122. MS (ES) [m+H] calc'd for C14H10FN3O6, 336; found 336.
Reaction SMILES: [Cl:1][C:2]([Cl:20])=[CH:3][CH2:4][O:5][C:6]1[CH:17]=[C:16]([Cl:18])[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14]O)=[C:8]([Cl:19])[CH:7]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]([Cl:20])=[CH:3][CH2:4][O:5][C:6]1[CH:17]=[C:16]([Cl:18])[C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:22])=[C:8]([Cl:19])[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
A stirred solution of 22.3 grams (0.062 mole) of 4-[4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenoxy]butan-1-ol and 20.6 grams (0.062 mole) of carbon tetrabromide in 250 mL of methylene chloride was cooled to 10° C. and 17.9 grams (0.068 mole) of triphenylphosphine was added in one portion. Upon completion of addition the reaction mixture was warmed to ambient temperature where it stirred during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 25% methylene chloride in hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 21.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11](Cl)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[N:21]1([C:27]2[CH:36]=[N:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)(C)C>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:24]2[CH2:25][CH2:26][N:21]([C:27]3[CH:36]=[N:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[CH2:22][CH2:23]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)O[C@H](C)c1nccc(N2CCN(c3cnc4ccccc4n3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 7.3 g, 36.2 mmol) in isopropanol (240 mL) was added triethylamine (10.1 mL, 72.4 mmol) followed by 2-(1-piperazinyl)quinoxaline (10.1 g, 47.1 mmol; J. Med. Chem. 1981, 24, 93). This mixture was stirred at room temperature overnight then concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (5×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (2% methanol/chloroform) to give 12.4 g (91%) of the title compound of Example 1, Step A as a yellow foam. 1H NMR (CDCl3, 250 MHz) δ8.61 (s, 1H), 8.27 (d, 1H), 7.91 (dd, 1H), 7.72 (dd, 1H), 7.61 (td, 1H), 7.44 (td, 1H), 6.43 (d, 1H), 5.70 (q, 1H), 3.96-3.84 (c, 8H), 2.18 (s, 3H), 1.61 (d, 3H); MS (CI/NH3) 379 (MH+).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15].N1C=CN=C1.S(=O)(=O)(O)O>CN(C)C=O.CCOCC>[Si:1]([O:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(CO)c1
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.7 %

Procedure:
33.3 g of tert-butyldimethylsilyl chloride is added to a solution of 30 g of 3-hydroxymethylbenzyl alcohol and 30 g of imidazole in 250 ml of dimethylformamide at 0° C. under argon and stirred for 20 hours at 25° C. It is diluted with 1.5 1 of ether, shaken twice with 100 ml of 10% sulfuric acid each, washed neutral with brine, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/0-80% ether, 23.4 g of 3-tert-butyldimethylsilyloxymethyl-benzyl alcohol is obtained as colorless oil.