Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C>CO>[N:15]1([CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (5.77 g, 91.6 mmol) to a solution of 4-cyanobenzaldehyde (3 g, 22.9 mmol), piperidine (5.84 g, 68.7 mmol) and acetic acid (2.75 g, 45.8 mmol) in methanol (30 mL) at 0° C. with stirring. Warm the mixture to room temperature and stir overnight. Add water (100 mL), saturated aqueous K2CO3 (50 mL), and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (400 g) eluting with hexane/EtOAc (1:0 to 4:1 gradient) to obtain the desired intermediate as a clear oil (2.48 g, 54%). MS (APCI+) m/z: 201 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:17][C:18]([C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH2:32][CH2:33]O)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.[OH-].[Na+]>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[S:24][C:20]3[C:18](=[O:19])[N:17]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][N:12]5[CH2:13][CH2:14][CH2:15][CH2:16]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:33]=[CH:32][C:21]=3[N:22]=2)=[CH:26][CH:27]=1
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CCO)ccc1OCCN1CCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.6 %

Procedure:
Mix 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid [3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide (80 mg, 0.16 mmol) and Dess-Martin periodinane (70 mg, 0.1 6 mmol) in CH2Cl2 and stir at RT for 48 h. Dilute the mixture with aqueous 1 N NaOH and extract with CH2Cl2. Dry, filter, and concentrate the organic solution. Purify the crude material by flash chromatography, using a gradient of 100% EtOAc to 12% 2 N NH3/MeOH in EtOAc, to give the title compound (12 mg, 16%). MS (ES+) 482.0 (M+1)+. 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, 2H, J=8.8 Hz), 7.46 (d, 2H, J=8.3 Hz), 7.40 (d, 1H, J=7.0 Hz), 7.34 (s, 1H), 6.89-6.99 (m, 3H), 4.20 (t, 2H, J=6.4 Hz), 3.86 (s, 3H), 2.96 (t, 2H, J=6.4 Hz), 2.64 (s, 4H), 1.80 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.[C:26]([CH2:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30])#[N:27].C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O>>[C:26]([CH2:28][S:29]([CH2:32][C:33]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:34])(=[O:31])=[O:30])#[N:27]
Reactant: N#CCS(=O)(=O)CC(=O)O
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC#N)[C@H]2SC1

Procedure:
t-Butyl 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate (5.75 g, 15 mmol), cyanomethylsulfonylacetic acid (2.45 g, 15 mmol), and dicyclohexylcarbodiimide (3.1 g, 15 mmol) were reacted as in Example 6. The t-butyl ester was treated with trifluoroacetic acid for 20 minutes as in Example 6, to give the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[C:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:29][C:30]([NH2:32])=[O:31].O>CN(C=O)C>[C:15]([C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:29][C:30]([NH2:32])=[O:31])=[CH:21][CH:20]=3)[C:9]=2[C:10]([O:17][CH3:18])=[N:11][CH:12]=1)#[N:16]
Reactant: NC(=O)CBr
Reactant: COc1ncc(C#N)c2c1c(-c1ccc(O)cc1)cn2C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(C#N)c2c1c(-c1ccc(OCC(N)=O)cc1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To a solution of 1-cyclopentyl-3-(4-hydroxyphenyl)-4-methoxy-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (120 mg) and sodium hydride (dispersion in mineral oil, 22 mg) in DMF (3.0 mL) was added 2-bromoacetamide (120 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (37 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([C@@H:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@H:16](O)[CH2:15]3)=[CH:13][C:8]=2[O:7][CH2:6]1>ClCCl>[Cl:3][CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([C:12]2[CH:11]=[CH:10][C:9]3[O:5][CH2:6][O:7][C:8]=3[CH:13]=2)[CH2:15]1
Reactant: O=S(Cl)Cl
Reactant: O[C@@H]1C[C@H](c2ccc3c(c2)OCO3)c2ccccc21
Solvent: ClCCl
Product: ClC1CC(c2ccc3c(c2)OCO3)c2ccccc21

Procedure:
Thionyl chloride (7 mL) was added with stirring and cooling at 15° C. to a solution of cis-3-(benzo[1,3]dioxol-5-yl)-indan-1-ol (10 g) in dichloromethane (300 mL). The mixture was stirred at rt for 40 min. The mixture was washed twice with water, dried (MgSO4) and evaporated in vacuo to give a quantitative yield of 5-(3-chloroindan-1-yl)benzo[1,3]dioxole as an oil, which was used in the next step without further purification.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[NH:16][N:15]=2)=[CH:10][CH:9]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CN(C=O)C>[I:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[N:16]([CH2:26][CH:28]3[CH2:29][O:30]3)[N:15]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(I)cc3)c2C1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC2CO2)C1
Reaction time: 17 h
Yield: 57.6 %

Procedure:
Cs2CO3 (1.30 g, 4.01 mmol) was added to a solution of 1-[3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (1.34 g, 3.65 mmol) and epichlorohydrin (2.85 mL, 36.4 mmol) in DMF (10.0 mL). The mixture was stirred for 17 h then partitioned between EtOAc (400 mL) and saturated NaHCO3 (150 mL). The NaHCO3 layer was extracted with EtOAc (2×150 mL). The combined extracts were washed with H2O (2×150 mL), brine (150 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 10-25% acetone/CH2Cl2) to give 890 mg (58%) of the title compound. HPLC, tR=5.53 min. (Reverse phase conditions: HP 1100 LCMS, Phenomenex luna 2.1×150 mm column, 60% MeOH/H2O (0.5% AcOH) to 90% MeOH/H2O (0.5% AcOH), held at initial conditions for 2 min then ramped to final conditions over 5 min.) MS (electrospray), m/z calculated for C17H18IN3O2Na [M+Na]+ 445.04, found 445.95. 1H NMR (CDCl3, 500 MHz, a mixture of amide rotamers): 7.76 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 4.80 and 4.73 (A and B of AB quartet, Jab=15.6 Hz, 2H), 4.60 (s, 2H), 4.84 (dd, J=15.1, 2.1 Hz, 1H), 4.42 (dd, J=15.0, 2.1 Hz, 1H), 4.11 (t, J=5.0, Hz, 1H), 4.08 (t, J=5.0 Hz, 1H), 3.98-3.87 (m, 2H), 3.74 (m, 2H), 3.34 (m, 2H), 2.87-2.72 (m, 6H), 2.52 (dd, J=4.6, 2.6 Hz, 1H), 2.48 (dd, J=4.5, 2.6, 1H), 2.20 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:26]1[CH:27]=[CH:28][C:23]([CH:21]=[CH:22][C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][N:11]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C=Cc2ccncc2)c1
Yield: 68.9 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 54b (1.03 g, 3.0 mmol) in acetonitrile (20 mL) and triethylamine (12.5 mL) was added 4-vinylpyridine (0.65 mL, 6 mmol), palladium acetate (125 mg, 0.56 mmol) and tri-o-tolylphosphine (625 mg). The mixture was heated at reflux for 16 hours. The solvent was removed, and the residue was washed with saturated sodium bicarbonate was added to free the amine, and the mixture was extracted with EtOAc, dried (MgSO4), and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 1:2 to 0:1 to afford the title compound (760 mg, 69%). MS (CI/NH3) m/z 368 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.43 (s, 9H), 2.35 (m, 2H), 3.90 (m, 2H), 4.20 (m, 1H), 4.40 (m, 1H), 4.55 (m, 1H), 7.10 (m, 1H), 7.2 (m, 1H), 7.38 (m, 2H), 7.45 (br s, 1H), 8.29 (m, 1H), 8.37 (s, 1H), 8.61 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C.C1COCC1.[H][H]>[Pt].C(OCC)(=O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(O)cc2)cc1
Yield: 96.2 %

Procedure:
1-(4-Hydroxyphenoxy)-4-nitrobenzene X (8.93 g, 38.62 mmol), 0.5% platinum catalyst on activated charcoal (1.5 g), THF (100 mL), and ethyl acetate (20 mL) were charged into a 250 mL hydrogenation vessel. Hydrogenation was carried out under 60 psi of hydrogen at room temperature for 16 hr. The reaction mixture was filtered and the organic solvents were removed under reduced pressure at 40° C. to give 4-(4-aminophenoxy)phenol XI (8.10 g, 96.2% yield), mp 130°-4° C. The IR and 1H-NMR spectra agreed with the assigned structure.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[N:8][CH:9]=1.[CH3:16]I>CN(C)C=O>[Br:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][CH2:13][N:12]([CH3:16])[C:11]2=[O:15])=[N:8][CH:9]=1
Reactant: O=C1NCCN1c1ncc(Br)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc(Br)cn2)C1=O
Reaction time: 0.5 h

Procedure:
NaH (10 mg) was added to a solution of 1-(5-bromopyrimidin-2-yl)imidazolidin-2-one (50 mg) in N,N-dimethylformamide (5 mL) under nitrogen at 0° C. After stirring for 30 min, MeI (36 mg) was added. The reaction mixture was stirred at room temperature until the starting material was completely consumed (TLC). The reaction mixture was then quenched with H2O (20 mL) and the resulting mixture was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with H2O (3×20 mL), dried (Na2SO4), and concentrated. The residue was purified by preparative TLC to afford the title compound. Yield: 10 mg (19% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13]OC1C=CC(B(O)O)=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:24]([C:27]1[CH:32]=[CH:31]C(CCC(O)=O)=[CH:29][CH:28]=1)([OH:26])[OH:25].C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][CH2:12][C:13]1[CH:31]=[CH:32][C:27]([B:24]([OH:26])[OH:25])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCOc1ccc(B(O)O)cc1)OCc1ccccc1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: BrCc1ccccc1
Product: O=C(CCc1ccc(B(O)O)cc1)OCc1ccccc1
Yield: 62 %

Procedure:
Using a procedure analogous to that used to prepare 1B, 3-(4-boronophenyl)propanoic acid (388 mg, 2.00 mmol) was reacted with benzyl bromide to afford 4A (355 mg, 62%) as a white solid. 1H NMR (400 MHz, tetrahydrofuran-d8) δ 2.71 (t, J=7.9 Hz, 2H), 3.02 (t, J=7.5 Hz, 2H), 5.10 (s, 2H), 7.25-7.35 (m, 5H), 8.12 (d, J=7.9 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1>[Pd].C(O)C>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc2cc(N)ccc21
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A mixture of the nitroindole (D2) (5 g; 28.4 mM) and 5% palladium on charcoal in ethanol (300 ml) was hydrogenated at 60 p.s.i. (4.14×105Pa) at room temperature for 3 h. Removal of the catalyst by filtration followed by evaporation of the solvent gave the title compound (3.39 g; 95%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:6]([C:7]1[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccnc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccnc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a solution of 3-trimethylsilanylethynyl-pyridin-2-ylamine (28.1 g, 148 mmol.) described in Manufacturing Example 1-2-2 in tetrahydrofuran (300 mL) was added tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 20 mL, 20 mmol), which was stirred for 15 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate 4 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:1 then 1:2) to obtain the title compound (16.4 g, 93.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([OH:14])=[O:13]>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:11]([C:10]([OH:16])=[O:15])[C:12]([OH:14])=[O:13]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ccccc1C=O
Product: Cc1ccccc1C=C(C(=O)O)C(=O)O
Temperature: 90 °C

Procedure:
Combine 2-methylbenzaldehyde (39.6 g, 0.33 mol) and malonic acid (34.3 g, 0.33 mol). Heat at 90° C. for one hour, add 3.9 g of the aldehyde, and heat 6 hr. at 90°. Allow to cool, partition between diethyl ether and 1N NaOH, acidify the aqueous layer, filter off the solid, wash and dry to give the title compound as a beige solid, m.p. 197°-200°.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([OH:13])[CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[CH:1]1([CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCCC(O)CC1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCCC(=O)CC1CCCCC1
Yield: 73 %

Procedure:
A solution of 1-cyclohexyl-5-hexen-2-ol (2.75 g, 15 mmol; prepared according to X. Wang et al, in Org. Lett., 2003, 5, 2699, supplementary materials) in CH2Cl2 (5 ml) was added to a suspension of PCC (4.9 g, 22 mmol) and Celite® (7.35 g) in CH2Cl2 (70 ml) at 20°. After 4 hours at that temperature, 10 mol % of PCC was added and after a supplementary hour Et2O was added and the reaction filtrated over SiO2 before to be concentrated. Purification by chromatography on silica with cyclohexane/AcOEt 95:5 afforded the desired ketone in 73% yield.
Reaction SMILES: Cl.[CH3:2][C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH:23][C:24](=[O:27])[CH2:25]Cl)[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[O-][C:29]#[N:30].[Na+].C(=O)([O-])O.[Na+]>CS(C)=O>[NH2:30][C:29]1[N:13]2[C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:3]([CH3:5])([CH3:4])[CH3:2])=[CH:7][CH:8]=3)=[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:15][C:14]2=[N:23][C:24](=[O:27])[CH:25]=1
Reactant: CC(C)(C)c1ccc(-c2nc(NC(=O)CCl)sc2-c2ccncc2)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(-c2c(-c3ccncc3)sc3nc(=O)cc(N)n23)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 15.7 %

Procedure:
To a solution of N-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-2-chloroacetamide hydrochloride (1.0 g) in dimethylsulfoxide (5 mL) was added sodium cyanate (0.24 g). The mixture was stirred at room temperature for 14 hours. An aqueous solution of sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (1:1). The extract was washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure and the residue was purified with silica gel column chromatography (hexane-tetrahydrofuran, 1:1) and recrystallized from ethyl acetate to obtain the title compound (0.14 g, yield 24%).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCOCC1>[F:7][C:6]([F:9])([F:8])[CH2:5][CH:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][OH:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(CO)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NC(CO)CC(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
400 mg of rac-2-amino-4,4,4-trifluorobutan-1-ol (Example 42A, 2.5 mmol, purity about 90%, 1 equivalent) in 36 ml of 1,4-dioxane were admixed at RT with 0.38 ml of 50% aqueous potassium carbonate solution (1.7 mmol, 0.68 equivalent) and 0.54 ml of benzyl chloroformate (3.8 mmol, 1.5 equivalents), and the mixture was stirred at RT for 2 h. Then another 0.11 ml of benzyl chloroformate (0.76 mmol, 0.3 equivalent) and 0.08 ml of 50% aqueous potassium carbonate solution (0.35 mmol, 0.14 equivalent) were added and the mixture was stirred at RT for a further 30 min. Concentration under reduced pressure was followed by purification by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). The resulting crude product was taken up in ethyl acetate and washed twice with saturated aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over sodium sulphate, filtered and concentrated. 490 mg (70% of theory) of the title compound were obtained.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6]3([CH2:12][O:11]3)[C:5]=2[CH:4]=[N:3][CH:2]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][CH2:12][C:6]1([OH:11])[CH2:7][CH2:8][CH2:9][C:10]2[N:1]=[CH:2][N:3]=[CH:4][C:5]1=2
Reactant: COc1ccc(Br)c(O)c1
Reactant: c1ncc2c(n1)CCCC21CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccc(Br)c(OCC2(O)CCCc3ncncc32)c1

Procedure:
A solution of 10 mmol of 7′,8′-dihydro-6′H-spiro[oxirane-2,5′-quinazoline] and 15 mmol of 2-bromo-5-methoxyphenol [63604-94-4] in 30 ml of 2-propanol is admixed with 20 mmol of finely powdered potassium carbonate. The mixture is heated at reflux for 12-18 hours, cooled and filtered over Hyflo. The filtrate is evaporated and from the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9](Cl)[N:4]2[N:3]=1.[SH-:13].[Na+]>O>[NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([SH:13])[N:4]2[N:3]=1
Reactant: Cc1cc(Cl)n2nc(N)nc2n1
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(S)n2nc(N)nc2n1
Yield: 74.3 %

Procedure:
The product obtained in Step 1 (15 g) was added all at once at room temperature to a solution of 12 g of sodium hydrosulfide in 300 ml of water with stirring under a nitrogen stream. The mixture was stirred at room temperature for one hour, the insoluble matters were removed by filtration, the pH was adjusted to 1.0 with concentrated hydrochloric acid, and the formed crystals were collected by filtration and washed twice with 20 ml water, affording 11 g of the objective compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([S:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)(=[O:27])=[O:26])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)c(C)c1
Yield: 92 %

Procedure:
Sulfonylation of 1-(2,4-dimethylphenyl)piperazine (293 mg, 1.54 mmol) with naphthalene-2-sulfonyl chloride (350 mg, 1.54 mmol) was carried out according to a similar procedure described for example 3A using anhydrous dichloromethane (5 mL) as solvent and diisopropylethylamine (0.670 mL, 3.85 mmol) as base. 1-(2,4-dimethylphenyl)-4-(2-naphthylsulfonyl)piperazine was obtained in 92% yield (539 mg) as white solid.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[F:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH2:28][C:29]([OH:31])=[O:30])=[C:14]([CH3:27])[C:15]2=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[O:32][CH3:33].CO>CC(C)=O>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH2:28][C:29]([OH:31])=[O:30])=[C:14]([CH3:27])[C:15]2=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:7])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[O:32][CH3:33]
Reactant: O
Reactant: COc1cc2c(cc1F)C(=Cc1ccc(SC)cc1)C(C)=C2CC(=O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CO
Product: COc1cc2c(cc1F)C(=Cc1ccc(S(C)=O)cc1)C(C)=C2CC(=O)O
Temperature: 25 °C

Procedure:
A solution of sodium periodate, 4.28 g. (20 mole) in 40 ml. of water is added dropwise to 6-fluoro-5-methoxy-2-methyl-1-(ρ-methylthiobenzylidene)-3-indenyl acetic acid, 3.70 g. (10 mole) in 300 ml. methanol and enough acetone to cause solution. This solution is stirred over night at room temperature and filtered. The filtrate is evaporated at 30° to a small volume which causes the product to precipitate. The suspension is diluted with several volumes of water, cooled and collected. After rinsing with water and cold methanol-water (1:1), the product is dried in vacuo over potassium hydroxide pellets, and then in a vacuum oven at 70° C. The crude product is recrystallized from methylene chloride-petroleum ether to give 6-fluoro-5-methoxy-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenyl acetic acid (M.P. 190-193°).