Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH2:10][C:9](=[O:11])[C:8]([CH3:12])([CH3:13])[CH2:7][O:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: CC(=O)C(C)(C)COc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
36 g (0.159 mol) of 1-(4-chlorophenoxy)-2,2-dimethyl-butan-3-one were dissolved in 300 ml of chloroform, and 25.5 g (0.159 mol) of bromine were added dropwise at 20° C. in a manner such that continuous decolorization occurred. After the addition, the mixture was stirred at room temperature for 30 minutes and was then concentrated by distilling off the solvent in vacuo. 48.5 g (quantitative conversion) of crude 1-bromo-4-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were obtained as an oil.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].CCN(C(C)C)C(C)C>ClCCl>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:4]
Reactant: CCNCC
Reactant: O=C(Cl)C(Br)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)C(Br)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Bromo-phenyl-acetyl chloride (191.0 mmol) was taken up in anhydrous dichloromethane (150 mL) and the resulting mixture was cooled to 0° C. in an ice bath. Diethylamine (14.1 g, 191 mmol) was then added drop-wise over 15 minutes, following which DIPEA (24.7 g, 191 mmol) was added over 5 minutes. The reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was then washed with water, dried over MgSO4, filtered and concentrated to yield a dark brown colored oil. The oil was purified by silica gel chromatography to yield the title compound as a yellow oil.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[N:63]=[C:64]([O:66][CH2:67][CH2:68][O:69][CH3:70])[NH2:65]>CN(C)C=O>[CH3:70][O:69][CH2:68][CH2:67][O:66][C:64]1[N:65]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:63]=1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COCCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 300 mg (0.783 mmol) of the carboxylic acid from Example 56A in 10.0 ml of N,N-dimethylformamide were added, at room temperature, 329 mg (0.864 mmol) of HATU and 0.28 ml (205 mg, 1.59 mmol) of N,N′-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 106 mg (0.792 mmol) of 2-methoxyethyl N′-hydroxyimidocarbamate from Example 44A and stirred at room temperature overnight. The reaction solution was subsequently stirred at 120° C. for 2 h. The reaction solution was purified directly by means of preparative HPLC. Yield: 98.0 mg (26% of theory)
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.9 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.1 mg, 36.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.40–7.15 (m, 10H), 6.97 (d, 1H, J=7.6 Hz), 6.88–6.82 (m, 2H), 5.26 (m, 1H), 3.18 (m, 2H), 2.75 (m, 2H), 2.53 (m, 2H), 2.40–2.10 (m, 4H), 2.10–1.80 (m, 4H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 457.4 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([C:11]1[NH:12][NH:13][C:14]2[CH:20]=[CH:19][N:18]=[CH:17][C:15]=2[N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[ClH:1].[CH2:2]([C:11]1[NH:12][N:13]([C:21](=[O:23])[CH3:22])[C:14]2[CH:20]=[CH:19][N:18]=[CH:17][C:15]=2[N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCC1=Nc2cnccc2NN1
Agent: Cl
Product: CCCCCCCCCC1=Nc2cnccc2N(C(C)=O)N1
Temperature: 80 °C
Yield: 73 %

Procedure:
A mixture of 6 g (0.02 moles) of 1,2-dihydro-3-nonylpyrido[3,4-e]-as-triazine hydrochloride and 80 ml of acetic anhydride is maintained at 80° C. for 2 hours. The product separates upon cooling. 5 g (73%) of 3-nonyl-1-acetyl-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride are obtained; m.p.: 209°-210° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:13]1[CH:17]=[C:16]([NH2:18])[NH:15][N:14]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:9]([C:13]1[CH:17]=[C:16]([NH2:18])[N:15]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[N:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: Clc1ccnc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(N)n(-c2ccnc(Cl)n2)n1
Temperature: 70 °C
Yield: 35 %

Procedure:
A mixture of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), 3-(tert-butyl)-1H-pyrazol-5-amine (1.03 g, 7.4 mmol) and sodium carbonate (1.42 g, 13.4 mmol) in 1,4-dioxane was treated with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (58 mg, 0.10 mmol) followed by tris(dibenzylideneacetone)dipalladium (31 mg, 0.03 mmol). The mixture was degassed then heated to 70° C. under N2 for 5 h. After cooling to room temperature the mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-15% EtOAc in cyclohexane, to give the title compound (0.59 g, 35%). LCMS (Method 3): Rt 3.97 min, m/z 252.2 [MH+].
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=O)=[CH:16][C:3]1=2.S(Cl)([Cl:23])=O>>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([Cl:23])=[O:20])=[CH:16][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1O2
Product: O=C(Cl)Cc1ccc2c(c1)C(=O)Cc1ccccc1O2

Procedure:
2.68 g of (11-oxo-2-dibenz[b,f]oxepinyl)acetic acid is dissolved in 9.15 ml of thionyl chloride and heated for 3 hours under reflux. The mixture is then concentrated under vacuum, thus obtaining 3.04 g of (11-oxo-2-dibenz[b,f]oxepinyl)acetyl chloride. This acid chloride is reacted under the conditions of Example 2 with trimethyl phosphite, yielding 1.34 g of 2-(11-oxo-2-dibenz[b,f]oxepinyl)-1-hydroxyethenephosphonic acid dimethyl ester, mp 118° C. The resultant product is reacted with dimethyl phosphite as described in Example 1, yielding the 2-(11-oxo-2-dibenz[b,f]oxepinyl)-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester), mp 133° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:27][CH2:26][C:11]2[C:12]3[C:13]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:14][CH2:15][C:16]=3[C:17](I)=[CH:18][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH3:3].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[CH2:2]([O:4][C:5]([N:7]1[CH2:27][CH2:26][C:11]2[C:12]3[CH:13]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14][CH2:15][C:16]=3[CH:17]=[CH:18][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: [H][H]
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(c1cccnc1)=CC3
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(c1cccnc1)CC3
Yield: 54.8 %

Procedure:
Into a 500 ml Parr hydrogenation bottle, the product from step (b) (0.38 mmol) dissolved in EtOH (50 ml) was added. To the argon purged bottle, 100 mg of 20% Pd(OH)2 was placed. The bottle was shaken over hydrogen (50 psi) for 6 h. The reaction mixture was filtered through celite and solvent evaporated in vacuo. The residue was dissolved in DCM and washed with saturated aqueous Na2CO3. The DCM layer was dried over Na2SO4 and solvent was evaporated in vacuo to give the crude product that was purified by silica-gel chromatography (gradient elution: 0 to 80% EtOAc in hexane) to give the sub-title compound as a yellow oil (70 mg). MS: ESI (positive): 337 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH:7](C)[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].C(N(CC)CC)C>C1COCC1>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(N)C(O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NCC(O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A solution of 0.33 ml (0.975 g, 4.2 mmol) chloroacetyl chloride in 10 ml THF was cooled to 0° C. To this was added a solution of 0.8 g (3.98 mmol) 2-amino-1,1-diphenylpropanol and 0.6 ml (0.436 g, 4.31 mmol) triethylamine in 10 ml THF. The resulting solution was stirred at 0° C. for 2 hours before it was filtered and the residue washed with THF. The combined filtrate was concentration and the residue crystallized from ethyl acetate-hexane to afford 0.986 g (78%) of 2-(2-chloroacetylamino)-1,1-diphenylethanol, m.p. 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][C:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([O:23]CC)=[O:22])=[CH:14][CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].O.[OH-].[Li+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][C:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([OH:23])=[O:22])=[CH:14][CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc(C2=CCC(NC(=O)c3nc(Cl)c(CC)[nH]3)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1[nH]c(C(=O)NC2CC=C(c3cccc(C(=O)O)c3)CC2)nc1Cl
Yield: 20.1 %

Procedure:
The same operation as in Example (1i) was performed using ethyl 3-{4-[(4-chloro-5-ethyl-1H-imidazole-2-carbonyl)amino]cyclohex-1-enyl)benzoate obtained in Example (195d) (150 mg, 0.373 mmol) and lithium hydroxide monohydrate (156 mg, 3.73 mmol), to obtain 28 mg of the title compound as a white solid (20%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[CH2:19][NH2:20]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27])[CH2:19][NH:20][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: NCc1ccc(C(F)(F)F)c(Cl)c1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Product: COc1cccc2c(NCc3ccc(C(F)(F)F)c(Cl)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and 3-chloro-4-trifluoromethylbenzylamine.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][CH2:11][C:12]([CH3:23])([OH:22])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>>[I:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]2([CH3:23])[O:22][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:10][CH2:11]2)=[CH:16][CH:17]=1
Reactant: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Product: CC1(COc2ccc(I)cc2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 74 %

Procedure:
Ring closure of alcohol 143 with NaH (1.5 equiv.) as in Example 2AA, followed by chromatography of the product on silica gel, eluting with 0-33% EtOAc/petroleum ether (foreruns) and then with 0-5% EtOAc/CH2Cl2, gave 7-[(4-iodophenoxy)methyl]-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (144) (74%) as a pale yellow solid: mp (CH2Cl2/hexane) 170-172° C.; 1H NMR (CDCl3) δ 7.57 (dt, J=9.0, 2.7 Hz, 2H), 7.44 (s, 1H), 6.64 (dt, J=9.0, 2.7 Hz, 2H), 4.19-4.05 (m, 2H), 4.07 (d, J=9.6 Hz, 1H), 4.02 (d, J=9.6 Hz, 1H), 2.49 (ddd, J=14.5, 7.4, 6.0 Hz, 1H), 2.24 (ddd, J=14.5, 6.4, 5.9 Hz, 1H), 1.58 (s, 3H). Anal. (C14H14IN3O4) C, H, N.
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[C:1]([C:5]1[N:9]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:8]=[C:7]([C:10]([F:12])([F:13])[F:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(C)(C)c1cc(C(F)(F)F)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-tert-Butyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) 6.94–7.08 (t, 2H), 6.82–6.88 (dd, 2H), 6.32 (s, 1H), 5.14 (s, 2H), 3.62–3.80 (m, 4H), 3.05–3.18 (m, 4H), 1.35 (s, 9H). MS (ES) M+H expected 412.43, found 413.1
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[CH2:31]([O:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH:41]=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CO>[CH2:31]([O:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1/[CH:41]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][N:3]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CO
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium bromide (150 mg, 0.32 mmol) was dissolved in methanol (2 mL) and the solution was added with o-benzyloxybenzaldehyde (55 μL, 0.35 mmol) and potassium carbonate (88 mg, 0.63 mmol), followed by stirring at room temperature for 2 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. Then, the organic layer was sequentially washed with water and saturated brine, and was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in a mixed solvent of ethyl acetate/hexane (2/1) to obtain Compound 13 (39.3 mg, 38%).
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[F:19])[CH2:6][CH2:5]1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:23][CH:9]1[C:4](=[O:3])[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[F:19])[CH2:8]1
Reactant: C[Si](C)(C)OC1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2F)CC1F
Reaction time: 4 h
Yield: 88 %

Procedure:
The mixture of 4-(4-trimethylsilyloxy-piperidin-1-yl)-3-fluoronitrobenzene (151 mmol), selectfluor (151 mmol) in acetonitrile was stirred for 4 hours. The solvent was removed under reduced pressure and to the residual mass was extracted into ethyl acetate water mixture. The combined organic layer was dried and removal of the solvent afforded title compound in 88% yield.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[Mn]([O-])(=O)(=O)=[O:20].[K+]>N1C=CC=CC=1>[CH3:18][Si:2]([CH3:1])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([OH:20])=[O:7]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCCCC[Si](C)(C)CCCCO
Agent: [K+]
Solvent: c1ccncc1
Product: CCCCCCCCCC[Si](C)(C)CCCC(=O)O
Reaction time: 30 h

Procedure:
To a solution of 25.0 g (91.7 mmol; 366.8 electron equivalents) of 5,5-dimethyl-5-sila-n-pentadecanol in 100 ml of pyridine, is added 21.5 g (136 mmol; 408 electron equivalents) of potassium permanganate in 320 ml of pyridine, at 20°-25° with stirring, and stirring is continued for 30 hr. A dark brown precipitate forms which is filtered off (leaving a colorless filtrate). The filter cake is thoroughly washed with methanol and ligroine. The washes and filtrate are combined and concentrated to near dryness. The residue is added to a mixture of water, ice, petroleum ether and dilute hydrochloric acid and the organic phase recovered. The aqueous phase is washed once with petroleum ether, which wash is then combined with the previously recovered organic phase, and the combined organic phases washed thrice with water, dried, and then concentrated to obtain crude title product, which is refined by distillation through a Vigreux column, b.p. 142°-132° at 0.145-0.115 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([NH2:21])=[CH:16][C:15]=2[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([F:22])=[CH:16][C:17]([NH:21][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[CH:18][C:19]=2[F:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N)cc2F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 0 °C
Yield: 89.4 %

Procedure:
To a solution of 4-(4-amino-2,6-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Intermediate III) (25 g, 0.08 mol), in 1:1 acetone:water (300 mL) was added sodium bicarbonate (15.1 g, 0.18 mol). The resulting solution was cooled to 0° C. and benzyl chloroformate (40 mL, 0.24 mol, 50% solution in toluene) was added dropwise. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (500 mL). The organic layer was washed with water (2×50 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2:3 ethyl acetate:Pet. ether) to provide title compound (32 g, 90%) as off white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(Nc2ccc(C#N)cc2)c1

Procedure:
2 g of 3-fluoro-4-nitroanisole and 15 ml of 4-aminobenzonitrile were stirred for 22 hours at 140° C. The batch was then diluted with ethyl acetate, washed three times with 2N aqueous hydrochloric acid, three times with water and once with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][C:16](C#N)=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH4+].[OH-]>CO.C1COCC1.[Ni]>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2nc3cc(C#N)ccc3s2)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 110.8 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-5-carbonitrile (500 mg, 1.75 mmol) in MeOH-THF (66 mL, 3:5) was added NH4OH (7 mL) and Raney Ni (100 mg). The mixture was stirred for 12 h at rt under a H2 atmosphere. The mixture was filtered and the filtrate was concentrated to give 5-aminomethyl-[2-(4-isopropylpiperazin-1-yl)benzothiazole 507 mg (100%), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:11]([Cl:12])=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[C:8]([CH:22]2[C@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:26]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:25]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[O:23]2)[C:3]=1[O:4][CH2:5]CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:80]([Cl:84])(Cl)(Cl)Cl>>[CH2:45]([O:44][C@H:25]1[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]([C:8]2[CH:9]=[C:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[C:11]([Cl:12])=[C:2]([Br:1])[C:3]=2[O:4][CH2:5][CH2:80][Cl:84])[O:23][C@@H:24]1[CH2:52][O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCO)c(Br)c2Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCl)c(Br)c2Cl)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of the intermediate 33 (3.04 g, 3.41 mmol) were added triphenylphosphine (2.23 g, 8.52 mmol) and CCl4 (3.7 mL). After stirring for 2 h at 55° C., the solvent was evaporated off. The residue was dissolved in EtOAc (100 mL), washed with saturated NaHCO3 solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 34 (1.62 g, 1.78 mmol, 52%).