Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].CC1C=CC(S(O[CH2:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Temperature: 70 °C
Yield: 98.7 %

Procedure:
4-Bromo-3,5-dimethylphenol (40.00 g), 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (72.71 g) and potassium carbonate (35.75 g) were added to N,N-dimethylformamide (400 mL), and the mixture was stirred. The mixture was heated to 70° C., stirred for 46 hr, and cooled to 5° C. Water (200 mL) was added dropwise at 10° C. or below, seed crystal (60 mg) was added, and water (400 mL) was continuously added. After stirring for 2 hr, the precipitated crystals were collected by filtration, washed with water (400 mL) and dried to give the title compound (63.08 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](C(O)=O)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][S:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cc(C(=O)O)sc1-c1ccccc1
Agent: O=C=O
Product: Cc1ccsc1-c1ccccc1

Procedure:
The 4-methyl-5-phenyl-2-thiophenecarboxylic acid (127 g, 0.58 mol) prepared as described above was heated to 220–230° C. until the evolution of carbon dioxide ceased. The product was collected and distilled, b.p. 120° C./10 torr. Yield 30.3 g (30%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:15][C:14]([C:31](=[O:33])[CH3:32])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)=[CH:15][C:14]([CH:31]([OH:33])[CH3:32])=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)O)cc3c2CCNCCCCc2ccncc2)c1
Reaction time: 0.75 h
Yield: 88.5 %

Procedure:
To a solution of 1-{2-(3,5-dimethylphenyl)-3-[2-(4-pyridin-4-yl-butylamino)ethyl]-1H-indol-5-yl}ethanone (45 mg in 2 mL dry tetrahydrofuran) at 0° C. was added 0.30 mL of a 1M solution of lithium aluminum hydride in tetrahydrofuran and the mixture stirred at low temperature. After 45 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and the mixture extracted with ethyl acetate. The organic portion was washed with brine, dried over sodium sulfate and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:10:0.25) to give the title compound (40 mg). m/e=442 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:21]3[CH2:27][CH:26]4[NH:28][CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[C:15](Br)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:21]3[CH2:27][CH:26]4[NH:28][CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[C:15]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(Br)cccc1C2=C1CC2CCC(C1)N2
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(cccc1-c1ccccc1)C2=C1CC2CCC(C1)N2
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-5-bromo-9H-xanthene-3-carboxylic acid diethylamide (0.170, 0.363 mmol), phenylboronic acid (0.049 g, 0.40 mmol) and cesium carbonate (0.236 g, 0.726 mmol) in dioxane (4 mL) and ethanol (1 mL) was treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (13 mg), and the resulting mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, and the inorganics removed by filtration and washed successively with dioxane, ethanol and dichloromethane. The solvents were evaporated in vacuo. The residue was purified by reverse phase (C18) preparative HPLC, using a gradient of acetonitrile (10% to 90%) in water with trifluoroacetate (0.1%) as the eluant to give the title compound (0.153 g) as a colorless solid. MS: m/z 465.3 (MH+). 1H NMR (DMSO-d6): δ 1.05-1.20 (br m, 6 H0, 1.31 d, 2 H, J=8.2 Hz), 1.75-1.85 (br m, 2 H), 2.90-3.10 (m, 4 H), 3.15-3.50 (br m, 4 H), 4.03 br s, 2 H), 7.10 (d, 1 H, J=1.5 Hz), 7.20 (d of d, 1 H, J=1.5 & 7.9 Hz), 7.32 (t, 1 H, J=7.5 Hz), 7.40-7.63 (m, 8 H), 8.83 (br s, 1 H0 and 9.16 (br d, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrC1CCCC1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C3CCCC3)CC1)O2

Procedure:
Compound 138 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, bromocyclopentane and conditions outlined in procedure V. LCMS: 370 [M+H]; Rt=0.90 min.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>CN(C)C=O>[C:23]([OH:28])(=[O:29])[CH2:24][CH2:25][C:26]([OH:14])=[O:27].[C:7]1([C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[C:7]1([C:13]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[OH:16])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)O1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)O
Reaction time: 8 h

Procedure:
A clean dry reactor of 20 gallon capacity (91 liters) was charged with pyridine (7.0 kg.) followed by dimethylformamide (35.5 kg.). With agitation, benzoin (18.80 kg.) and succinic anhydride (16.0 kg.) were added. The reactor was flushed with nitrogen. Under a continuing atmosphere of nitrogen, the mixture was heated to 90°-95° C. and maintained within this temperature range for 2 hours. The reaction mixture was cooled to 35°-40° C. After twenty minutes, the reaction mixture was tranferred gradually over 5 hours to a mixture of water (190 kg.) and hydrochloric acid of specific gravity 1.18 (28 kg.) at 55°-60° C. in a reactor of 50 gallon capacity (227 liters). The temperature was maintained at 50°-60° C. over the 5 hour period. Dimethylformamide (9.0 kg.) was used for washing through. The mixture was cooled slowly until product crystallised and then to 15° to 20° C. The mixture was stirred overnight at 15° to 20° C. The product was filtered on a ceramic filter and sucked well dry. The product was then washed with water ten times with 20 kg. each time. Ater each wash portion the product was sucked well dry. The product was then dried in a circulating air oven at 50°-60° C. for 12 to 18 hours. The yield obtained was 25.5 kg.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=[CH:9]2.S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([N+:1]([O-:4])=[O:2])=[C:11]([O:16][CH3:17])[CH:10]=[CH:9]2
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
An ice-cooled solution of 100% nitric acid (12.0 ml, 0.27 mol) in 95 ml of acetic anhydride was added dropwise to a solution of 6-bromo-2-methoxynaphthalene (61.7 g, 0.26 mol) and 0.25 ml of conc. sulfuric acid in 570 ml of acetic anhydride while maintaining the temperature at +30° to +40° C. The mixture was stirred for an additional 10 min. and filtered. The solid was washed with water and dried to give 60.0 g (73%) of the nitro compound. M.p. 151°-152° C., 1H-NMR (CDCl3): 3.98 (s, 3H, CH3), 7.16-7.93 (m, 5H, ArH).
Reaction SMILES: [Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]([C:18]2[C:19]([Cl:25])=[N:20][CH:21]=[N:22][C:23]=2Cl)=O)[C:9]=1[F:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:27][NH2:28]>C1COCC1.O.CCOC(C)=O>[Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]2[C:18]3[C:23](=[N:22][CH:21]=[N:20][C:19]=3[Cl:25])[NH:28][N:27]=2)[C:9]=1[F:26])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(=O)c2c(Cl)ncnc2Cl)c1F
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(-c2n[nH]c3ncnc(Cl)c23)c1F
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
[4-[tert-butyl(dimethyl)silyl]-3,5,6-trifluoro-2-pyridyl]-(4,6-dichloropyrimidin-5-yl)methanone (901 mg, 2.13 mmol) was dissolved in THF (18 mL) and cooled to −50° C. Hydrazine (1M in THF) (2.20 mL of 1 M, 2.20 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then allowed to warm to ambient temperature for 30 minutes. The reaction mixture was diluted with water and EtOAc. The organic layer was separated, washed with water (2×), brine, dried (MgSO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 80 g column, eluting with 0-3% MeOH/DCM) to give the sub title compound as an orange foam (498 mg, 58.4% Yield). H1 NMR (400 MHz, DMSO) δ 15.04 (1H, s), 8.92 (1H, s), 0.95 (9H, s) and 0.44 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH:12]([CH:14]1[CH2:16][CH2:15]1)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:12][CH:14]2[CH2:16][CH2:15]2)[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: OC(Br)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccc(Cl)cc1OCC1CC1
Temperature: 80 °C
Yield: 13.1 %

Procedure:
Charged 5-chloro-2-(hydroxymethyl)phenol (616 mg, 3.88 mmol, PREPARATION 7), bromocyclopropylmethanol (525 mg, 3.88 mmol), K2CO3 (1.07 g, 7.77 mmol) and DMF (6 mL) to a flask, purged with nitrogen and heated to 80° C. overnight. Poured into ice water, and extracted with ethyl acetate twice, and washed the organic phase with water twice, brine and dried with anhydrous Na2SO4, removed the solvent for silica gel chromatograph to give 108 mg of the title compound (13%). 1H NMR (400 MHz, CDCl3): δ 0.33-0.37 (2H, m), 0.63-0.68 (2H, m), 1.26-1.28 (1H, m), 3.84 (2H, d, J=7.2 Hz), 4.67 (2H, s), 4.86 (1H, s), 6.84 (1H, d, J=1.2 Hz), 6.91 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.19 (1H, d, J=7.6 Hz).
Reaction SMILES: [CH3:1][N:2]([CH2:13][C@@H:14]([NH:23]C(=O)OC(C)(C)C)[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:23][C@@H:14]([CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[CH2:13][N:2]([CH3:1])[C:3](=[O:4])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C[C@H](CC1CCC(=O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C[C@@H](N)CC1CCC(=O)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl 1-(N-methyl-N-(benzyloxycarbonyl)amino)-3-(4-oxocyclohexyl)propan-2-ylcarbamate (300 mg, 0.72 mmol) was dissolved in 5 mL of 20% TFA/CH2Cl2 and stirred 1 hr at rt. The solvent was removed to give the crude (S)-benzyl 2-amino-3-(4-oxocyclohexyl)propyl(methyl)carbamate, which was used directly for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:13](I)[CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: CCCI
Product: CCCOc1ccc(C(=O)O)c(Cl)c1

Procedure:
Using methyl 2-chloro-4-hydroxybenzoate and propyl iodide, 2-chloro-4-propoxybenzoic acid was obtained in the same manner as in Example 277b).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: N#Cc1cc(C=O)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(CO)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
To the solution of 2-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}-5-formylbenzonitrile (1.74 g, 5.63 mmol) in ethanol (40 ml), was added NaBH4 (0.255 g, 6.75 mmol). The solution was stirred at room temperature under nitrogen for 1.5 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice. The solvent was dried over Na2SO4, concentrated to afford the title compound (1.23 g, 70% yield) as a green solid. LCMS: rt=3.06 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O.[NH2:16][CH2:17][CH2:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1.ClC(OCC)=O>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]([CH3:30])([CH3:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:32][CH:33]=1)=[O:10]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: COc1cccc(OC(C)(C)C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)C(C)(C)Oc2cccc(OC)c2)cc1
Yield: 84 %

Procedure:
In a manner analogous to that described in Example 4, from 2-(3-methoxyphenoxy)-2-methylpropionic acid and ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate, in the presence of triethylamine and ethyl chloroformate, there is obtained, in a yield of 84% of theory, ethyl 2-{{4-{2-[2-(3-methoxyphenoxy)-2-methylpropionylamino]-ethyl}-phenoxy}}-2-methylpropionate which, after recrystallization from cyclohexane and ethyl acetate, melts at 68°-69° C. and from this 2-{{4-{2-[2-(3-methoxyphenoxy)-2-methylpropionylamino]-ethyl}-phenoxy}}-2-methylpropionic acid in a yield of 64% of theory which, after recrystallization from cyclohexane and ethyl acetate, melts at 80°-81° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][NH:17][CH3:18].O.[BH4-].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:17]([CH3:18])[CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: CNC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(CN(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 4-(diethoxymethyl)benzaldehyde (6.8 g, 32.69 mmol) and dimethylamine in 33 wt. % solution in water (9.25 g, 98 mmol) in methanol (200 mL) was stirred at room temperature for overnight. Sodium borohydride (1.85 g, 49 mmol) was added by portions with ice cooling. After the addition, the mixture was stirred at room temperature for 4 hr. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 ml×3). The extract was dried over anhydrous sodium sulfate and concentrated to give crude title compound (7.0 g, yield 90%), which was used in the next step without further purification. LC-MS (ESI) m/z: 238 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][N:14]=3)[O:8][C:4]=2[CH:3]=1.CN(C=O)C.C1C(=O)N([Br:30])C(=O)C1>C(OCC)(=O)C>[Br:30][C:13]1[N:14]=[C:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([F:1])[CH:17]=[CH:16][C:5]=3[N:6]=2)[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: Nc1nccnc1-c1nc2ccc(F)cc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ncc(Br)nc1-c1nc2ccc(F)cc2o1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-(6-Fluoro-1,3-benzoxazol-2-yl)pyrazin-2-amine (300 mg) was dissolved into DMF (15 ml) at 50° C. N-bromosuccimide (325 mg) was added. The mixture was stirred at 40° C. for 2 hours. The resulting mixture was diluted with ethyl acetate (15 ml), and washed with brine (10 ml×3). The organic layer was dried and concentrated to give 5-bromo-3-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-amine, which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:20]1([C:26]2[N:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32]([C:29]3[CH:28]=[CH:27][C:26]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:31][CH:30]=3)=[O:33])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1ccc(N2CCOCC2)nc1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 78.2 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (80 mg, 0.272 mmol) in DMF (5 ml) were added 6-(4-morpholinyl)-3-pyridinecarboxylic acid (56.6 mg, 0.272 mmol), HOBT.H2O (41.6 mg, 0.272 mmol), HBTU (103 mg, 0.272 mmol) and DIPEA (0.142 ml, 0.816 mmol) and the reaction mixture was stirred at room temperature for 2 h. The DMF was evaporated in vacuo then 5 ml of DCM were added and washed with saturated aqueous NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were collected and concentrated under vacuo giving the title compound (103 mg).
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17]C#N.CC[O-].[Na+].[Na]>O.C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([CH2:17][C:16]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:9])[CH:3]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: COc1ccc(CC#N)cc1OC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COc1ccc(CC(=O)c2cccnc2)cc1OC

Procedure:
A mixture of 45.4 g of ethyl nicotinate and 35.4 g of 3,4-dimethoxybenzyl cyanide is added dropwise to a boiling solution of sodium ethylate prepared from 6 g of sodium and 100 ml of ethanol. The mixture is kept at reflux for 5 hours and, after cooling, is poured into 1 liter of water. The excess nicotinic ester is removed with toluene, and the aqueous solution is neutralized with glacial acetic acid, 50.7 g of α-cyano-3,4-dimethoxybenzyl 3-pyridyl ketone separating out as crystals (melting point 149°-152° C.). This cyanoketone (31.0 g) is hydrolyzed in 6N hydrochloric acid at 80°-90° C. The hydrochloride of the 3,4-dimethoxybenzyl 3-pyridyl ketone crystallizes from ethanol with melting point 188°-191° C. and the free base has a melting point of 60°-64° C. The compound is converted into the oxime without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[C:18](=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]2[C:13]([C:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:12]3)[C:8]1=[O:9])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].ClCC(OCC=[CH:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=O>CN(C)C=O>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[C:18](=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]2[C:13]([C:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:12]3)[C:8]1=[O:9])=[O:5])[CH:2]=[CH:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CCOC(=O)CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Reactant: O=C(CCl)OCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O)OCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A similar procedure (Hursthouse, M. B.; Khan, A.; Marson, C. M.; Porter, R. A. Tetrahedron Lett. 1995, 36, 33, 5979-5982) to that described for the preparation of 207 was followed using NRB (0.49 g, 1.0 mmol) and potassium carbonate (0.33 g, 2.4 mmol) in dimethylformamide (5 mL), and cinnamyl chloroacetate (0.3 g, 1.4 mmol) in dimethylformamide (2 mL), and the mixture stirred at room temperature for 2 h. Purification by flash chromatography (hexane/ethyl acetate 3:2) afforded 371 as a white solid (0.63 g, 0.9 mmol, 90%). 1H NMR (400 MHz, CDCl3) δ 3.40-4.55 (8H, m, CH2CH═CH, NCH2, H-1, H-2, H-3, H-4), 5.48 (0.5H, s, OH), 5.52 (0.3H, m, V/H-6), 5.53 (0.5H, s, OH), 5.55 (0.4H, m, Y/H-6), 6.03 (0.1H, m, U/H-6), 6.05 (0.2H, m, W/H-6), 6.21-6.29 (1H, m, CH2CH═CH), 6.60-7.60 (22H, m, CH2CH═CH, Ar), 8.40-8.60 (2H, m, αPyr).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:27][C:28]([C:30]2[N:31](COCC[Si](C)(C)C)[CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]>C(Cl)Cl.CCO>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CCN(CCN3CCOCC3)CC2)cc1C1=CCCCC1
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(CCN4CCOCC4)CC3)cc2C2=CCCCC2)n1
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amide (650 mg, 1.05 mmol) (as prepared in the previous step) in 10 mL of DCM was added 0.3 mL of EtOH and 3.0 mL of TFA, and the reaction was allowed to proceed for 2 h at 25° C. The reaction was diluted with 10 mL of EtOH and concentrated. The title compound was purified by RP-HPLC (C18), eluting with 30-50% CH3CN in 0.1% TFA/H2O over 9 min to give 600 mg (80%) of a white solid. 1H-NMR (400 MHz, CD3ID): δ 8.18 (d, 1H), 8.04 (s, 1H), 7.24 (dd, 1H), 7.14 (d, 1H), 5.84 (m, 1H), 3.84 (m, 4H), 3.76 (m, 2H), 3.50 (m, 2H), 3.30-3.10 (m, 4H), 2.92 (m, 5H), 2.30 (m, 4H), 2.20-2.00 (m, 4H), 1.90-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C28H36N6O2, 489.2, found 489.2.