Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1>O1CCCC1>[F:28][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C@H:10]3[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9]3)[CH2:14][CH2:15]2)[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CCCBr
Reactant: Fc1ccc(CC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of tetrahydrofuran (hereafter referred to as "THF") to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.4 g of 1-chloro-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-silacyclohexane. The silacyclohexane rings of the product thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 5.8 g (yield 80%) of trans-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-n-propyl-1-silacyclohexane.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[CH3:16][NH:17][CH2:18][CH2:19][CH3:20].[I-].[K+]>CC(C)=O>[CH3:12][C:11]([CH3:14])([CH3:13])[C:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][N:17]([CH3:16])[CH2:18][CH2:19][CH3:20])[N:8]=1)=[O:15]
Reactant: CCCNC
Reactant: CC(C)(C)C(=O)Nc1cccc(CCl)n1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(C)Cc1cccc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C

Procedure:
N-(6-chloromethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.66 g), methyl-propylamine (0.33 mL), KHCO3 (0.32 g) and a catalytic amount of potassium iodide in acetone (10 mL) were heated to reflux for 6 h. The-reaction mixture was cooled to RT and partitioned between water and AcOEt, the layers were separated, the organic layer dried over MgSO4, filtered and evaporated to give 2,2-dimethyl-N-{6-[(methyl-propyl-amino)-methyl)-pyridin-2-yl}-propionamide (0.75 g) as a brown oil. MS (ESI): 264.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29][CH3:30])=[O:28])[CH:6]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Brc1cn[nH]c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Cn2cc(Br)cn2)c1
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol) in DMF (11.7 mL) at 0° C. was added 1 M solution of NaHMDS in THF (7.48 mL, 7.48 mmol) slowly over 2 min. The reaction mixture was stirred for 10 min and then the cooling bath was removed. After 30 min a solution of methyl 3-(bromomethyl)benzoate (1.71 g, 7.48 mmol) in DMF (1.9 mL) was added slowly, and the resulting mixture was stirred at room temperature overnight. At the conclusion of this period, the reaction mixture was quenched with saturated aq ammonium chloride (˜1 mL), and partitioned between diethyl ether and water. The resulting mixture was stirred vigorously for 15 min. After this time, the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-60% ethyl acetate:hexanes) to afford the title compound (1.59 g, 79%). LCMS, [M+H]+=295.0. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=7.1 Hz, 1H), 7.94 (s, 1H), 7.50 (s, 1H), 7.47-7.36 (m, 3H), 5.31 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [NH2:1][OH:2].Cl.[OH-].[K+].[O:6]1[CH2:12][CH2:11][C:10](=S)[NH:9][CH2:8][CH2:7]1.C(OCC)C>CO>[O:6]1[CH2:12][CH2:11][C:10](=[N:1][OH:2])[NH:9][CH2:8][CH2:7]1
Reactant: NO
Reactant: S=C1CCOCCN1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: ON=C1CCOCCN1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A solution of NH2OH HCl (2 eq.) in methanol was added to an equimolar methanolic solution of KOH. KCl was filtered off and the filtrate was added to a solution of 1,4-oxazepane-5-thione (1 eq.) in methanol. The mixture was stirred at 55° C. overnight, then cooled to room temperature and the solvent was removed under reduced pressure. The residue was taken in chloroform, washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give, after trituration with ethyl ether, the title compound. 1H NMR (300 MHz, CDCl3) δ 8.9 (bs, 1H), 6.15 (bs, 1H), 3.68-3.51 (m, 4H), 3.21-3.19 (m, 2H), 2.38-2.31 (m, 2H); MS (ES) C5H10N2O2 requires 130. Found: 131 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[C:4]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH:3]=1.C(O)C.CN>O>[NH2:11][CH2:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29]
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Solvent: O
Product: NCC#Cc1ccc(Cl)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Method B A mixture of 400 g (0.96 mole) of 1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopropyne, 1.3 L of ethanol and 300 ml of 40% aqueous methylamine was stirred at room temperature for 2 hr. Dropwise 2.8 l of water was added, and the resulting precipitate was collected by filtration to give a pale yellow solid, mp 70°-80° C. Recrystallization from ether gave pale yellow prisms, mp 80°-91° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[H][H]>[Pd].C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(N)cc1

Procedure:
Absolute ethanol (20 ml) was added to 10% palladium on charcoal (0.2 g) in a Parr hydrogenation bottle (500 ml volume). 1-(1,1-Dimethylethyl)-4-nitrobenzene (50 g) in absolute ethanol (100 ml) was added. Hydrogen was admitted to the bottle and the mixture shaken at 60 psi over night. The catalyst was removed by filtration through Celite under nitrogen, the filtrate was reduced in vacuo and the residue distilled at 96° C./0.3 mm Hg to give 4-(1,1-dimethylethyl)benzenamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:3]=12.[CH3:34]I>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:34])[CH:12]=3)=[CH:10][C:3]=12
Reactant: CI
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC

Procedure:
4-Chloro-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 89c, but using 7.1 g of 4-chloro-2-(5,6-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 1.10 ml of methyl iodide. After purification by flash chromatography (silica, 40/60 by volume ethyl acetate/cyclohexane as eluents, argon), 5.69 g of 4-chloro-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16](/[N:19]=[CH:20]/[C:21]4[O:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=4)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[O:4][C:3]1=[O:29].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[CH3:1][N:2]1[N:6]=[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][CH2:20][C:21]4[O:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=4)=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)[O:4][C:3]1=[O:29]
Reactant: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 85.9 %

Procedure:
3-Methyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9b, 0.40 g, 1 mmol) on reduction with sodiumcyanoborohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 3-methyl-5-[1-(4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10b, 343 mg, 86%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].CN(C)C=O.C[Si]([N:33]=[N+:34]=[N-:35])(C)C>[Cu]I.CO>[CH3:3][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:33]=[N:34][NH:35][CH:18]=3)[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:1]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (80 mg, 0.254 mmol) and copper(I) iodide (2.423 mg, 0.013 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and Methanol (0.200 mL). Trimethylsilyl azide (0.059 mL, 0.509 mmol) was added and the resulting mixture was stirred under microwave irradiation at 100° C. for 5 h then cooled to room temperature. The solution was partitioned between AcOEt and water/brine (1/1) and the layers were separated. The aqueous phase was extracted three times with AcOEt and the combined organic phases were washed with water then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified using MDAP (modifier: ammonium bicarbonate). The appropriate fractions were concentrated in vacuo and the residue dissolved in DCM. The organic phase was dried using a phase separator then concentrated in vacuo to give 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (30 mg, 0.084 mmol, 33.0% yield) as a white foam.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([C@@H:33]([CH2:43][CH3:44])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:29][CH:28]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:28]=[CH:29][C:30]([C@@H:33]([CH2:43][CH3:44])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[CH:31][CH:32]=1
Reactant: CC[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: CC[C@@H](CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(C)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 15 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (900 mg, 2.9 mmol) was reacted with (R)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (900 mg, 2.7 mmol) to afford the desired product (190 mg, 15%) as a yellow solid: ESI MS m % z 493 [C28H32N2O4S+H]+.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].O>CN(C)C=O>[CH3:1][S:2]([NH:5][CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: O=C(CCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)NCCC(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
Methanesulfonamide (0.476 g, 5.00 mmol) was dissolved in N,N-dimethyl-formamide (DMF, 10 mL), and 60% sodium hydride (0.275 g, 5.00 mmol) was added at 0° C., then the mixture was stirred at the same temperature for 20 minutes. Subsequently, to the mixture was added 3-chloropropiophenone (843 mg, 5.00 mol), and the mixture was stirred at the same temperature for 2 hours, and then further stirred at room temperature for 15 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to give N-methanesulfonyl-3-aminopropiophenone (240 mg, 21%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.I[CH:14]([CH3:16])[CH3:15]>CN(C=O)C>[I:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: CC(C)I
Reactant: Ic1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ncc2ccc(I)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (85 mg, 60%, 2.12 mmol) was added to an ice-cooled solution of 6-iodo-1H-indazole (249.5 mg, 1.02 mmol) in DMF (2.5 mL). After stirring this mixture for 1 h at 0° C., 2-iodopropane (0.32 mL, 3.2 mmol) was added and the mixture stirred at 100° C. for 16 h. After the reaction mixture was partitioned between water and ethyl acetate, the organic layer was washed sequentially with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Flash chromatography (silica gel, 5-20% ethyl acetate in hexane) yielded two products, the less polar 1-substituted-1H-indazole (105 mg) and the more polar 2-substituted indazolium (107.7 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18].[CH3:20][C:21]([CH3:23])=O>>[N+:14]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:21]([CH3:23])([CH3:20])[O:19][CH:17]([CH3:18])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(O)c1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Reactant: CC(C)=O
Product: CC1OC(C)(C)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 1-(4-amino-3′-nitro-biphenyl-3-yl)-ethanol and acetone in the same fashion as that of Example 4. Yellow solid: mp 188-189° C.; Anal. Calc. For C17H18N2O3.0.35H2O: C, 67.02; H, 6.19; N, 9.20. Found: C, 66.7; H, 5.89; N, 9.03.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:10]1[C:18](=[O:19])[C:16](=[O:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12]>>[OH:17][C:16]1([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:14](=[O:15])[NH:13][C:11](=[O:12])[NH:10][C:18]1=[O:19]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: c1ccc2scnc2c1
Product: O=C1NC(=O)C(O)(c2nc3ccccc3s2)C(=O)N1

Procedure:
By the procedure of Example 38, benzthiazole (2.7 g., 0.02 moles) was converted to its 2-lithio derivative and then reacted with anhydrous alloxan to yield title product, initially isolated as an oil. The latter was crystallized from ether-hexane [2.2 g.; Rf 0.55 (1:1 ethyl acetate:hexane/5% acetic acid)].
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
Trifluoroacetic acid (8 ml) was added to a solution of tert-butyl 4-(4-chlorobenzyl)piperazine-1-carboxylate (2.50 g, 8.05 mmol) prepared in Reference Example 178 in methylene chloride (16 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. Sodium hydroxide aqueous solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford 1-(4-chlorobenzyl)piperazine (1.70 g, quantitative) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:17][CH:18]([F:27])[O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[F:17][CH:18]([F:27])[O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-(difluoromethoxy)aniline in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CDCl3): δ 3.28 (s, 3H), 6.15-6.52 (m, 1H), 6.66-6.77 (m, 4H), 7.11-7.27 (m, 5H); Mass Spectrum: M−H+ 379.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[N:19]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].ClC1C=C(C(OO)=[O:41])C=CC=1>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]([S:28]([C:29]([F:31])([F:32])[F:30])=[O:41])=[CH:26][CH:27]=4)[N:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:4]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cnc(N2CCC(c3nc(COc4ccc(SC(F)(F)F)cc4)cs3)CC2)nc1
Solvent: ClCCl
Product: CCc1cnc(N2CCC(c3nc(COc4ccc(S(=O)C(F)(F)F)cc4)cs3)CC2)nc1
Reaction time: 1.5 h

Procedure:
To a solution of 5-Ethyl-2-{4-[4-(4-trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine (Example 16) in DCM at room temperature was added 3-chloro-benzenecarboperoxoic acid (2 eq.). The reaction was allowed to stir for 1.5 hours and an additional portion of 3-chloro-benzenecarboperoxoic acid (1 eq.) was added to the reaction mixture. The reaction was stirred at room temperature for an additional 4 hours. The organic solution was washed with sodium bicarbonate; the organic layer was isolated, dried over sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by column chromatography to afford the desired product. 1H NMR (DMSO-d6): δ 8.40 (2H, s), 7.58 (2H, d), 7.22 (1H, s), 7.02 (2H, d), 5.17 (2H, s), 3.74 (2H, m), 3.16 (1H, m), 2.96 (2H, m), 2.57 (2H, m), 2.22 (4H, m), 1.24 (3H, m).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:32]1([CH2:38][CH2:39][S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:46][C:45]1[CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[O:16][C:42](=[O:43])[C:41]=1[S:40][CH2:39][CH2:38][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)c1cccc(Oc2ccccc2)c1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(Oc3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-phenoxyacetophenone (2.00 g, 9.43 mmol), lithium bis(trimethylsilyl)amide (2.36 g, 14.15 mmol), chlorotrimethylsilane (1.79 mL, 14.15 mmol), THF (100 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 114°-115° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.76 (t, 2 H), 2.99 (t, 2 H), 6.76 (s, 1 H), 7.09 (m, 7 H), 7.34 (s, 1 H), 7.44 (t, 2 H), 7.56 (m, 2 H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10]([O:12]CC)=[O:11])[CH2:3]1.CO.[OH-].[K+]>O>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:3]1
Reactant: CCOC(=O)CC1CC(C)CC(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CC(C)CC(CC(=O)O)C1
Yield: 92.8 %

Procedure:
44.7 g of ethyl 3,5-dimethyl-cyclohexylacetate are treated with 300 ml of methanol and 15 g of potassium hydroxide, dissolved in 140 ml of water, and saponified by heating to reflux temperature for 3 hours. The working-up yields 35.6 g of a solid crude product which is used directly. A sample is distilled for the purpose of analysis.
Reaction SMILES: [Al](C)(C)C.[Cl:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[N:15]([Si](C)(C)C)=[N+:16]=[N-:17].Cl>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]1[NH:17][N:16]=[N:15][N:9]=1
Reactant: N#Cc1cccc(Cl)c1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2nnn[nH]2)c1Cl
Temperature: 80 °C

Procedure:
A 2.0 M solution of Al(CH3)3 in toluene (35 mL) was treated with 2,3-dichlorobenzonitrile (8.00 g, 37.2 mmol), azidotrimethylsilane (5.14 g, 44.6 mmol) slowly, and heated at 80° C. for 16 hours behind a blast shield. The mixture was cooled to 0° C. and treated with 2N HCl (100 mL) dropwise over 1 hour. The mixture was allowed to warm to ambient temperature and extracted twice with ethyl acetate (100 mL). The combined organic phases were dried over Na2SO4, filtered through a ½″ pad of silica gel, and the filtrate was evaporated under reduced pressure. The residue was purified by recrystallization from ethyl acetate/hexanes to provide the title compound. MS (DCI/NH3) m/z 215 (M)+; 1H NMR (DMSO-d6) δ 7.59 (t, 1H, J=8.0 Hz), 7.79 (dd, 1H, J=7.8, 1.7 Hz), 7.92 (dd, 1H, J=8.1, 1.7 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].[C:38](Cl)(=[O:40])[CH3:39].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:38]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9]([O:11][CH2:12][C:13]1([CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][CH2:15][O:14]1)=[O:10])(=[O:40])[CH3:39]
Reactant: CCCCCCCCCCCCCCCCCCOCC1(COC(=O)NCc2ccccn2)CCCO1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC1(COC(=O)N(Cc2ccccn2)C(C)=O)CCCO1

Procedure:
To 0.259 g (0.5 mmol) of the compound prepared in (b) above dissolved in 3 ml of chloroform was added, with stirring and under a nitrogen atmosphere, 0.393 g (5.0 mmol) of acetyl chloride. The resultant mixture was cooled in an ice bath and to the cooled mixture was added, dropwise, 0.51 g (5.0 mmol) of triethylamine. The resultant solution was then warmed to reflux and maintained at the reflux temperature for 2 hours. The volatiles were then removed under high vacuum and the resultant residue was dissolved in methylene chloride and washed rapidly with a saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulfate, filtered and concentrated. The resultant residue was then chromatographed on silica gel employing, successively as the eluents, a mixture of petroleum ether and ethyl acetate in a ratio of 4:1 by volume initially, with the product being eluted when the eluent was at a ratio of 7:3 by volume. The resultant solution was then concentrated to yield an oil.