Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccc(S(C)(=O)=O)cc2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
100 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 145 mg of 4-(methylsulfonyl)phenylboronic acid, 123 mg of sodium carbonate and 17 mg of tetrakis(triphenylphosphine)palladium were added in turn to a degassed mixed solvent of 3 ml of 1,4-dioxane and 1.2 ml of water, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 124 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)phenyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine as white powder. The obtained compound was dissolved in methanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective compound as white powder.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:39]1(I)[CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC3CCCC3)cc2n1Cc1ccccc1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 40 mg, 0.092 mmol) in DMF (1.0 ml) was reacted with K2CO3 (38 mg, 0.28 mmol), cyclopentyl iodide (53 μl, 0.46 mmol) to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)Cl
Reactant: CCCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCCN1CCC(c2c[nH]c3ccc(NC(=O)CC)nc23)CC1
Yield: 281.7 %

Procedure:
Beginning with 0.15 gm (0.55 mMol) 5-amino-3-(1-BUTYLPIPERIDIN-4-yl)pyrrolo[3,2-b]pyridine and 0.058 mL (0.067 mMol) propionyl chloride, 0.062 gm (35%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5]I)[CH3:2].[Li].[CH3:20][C:21](=[O:27])[CH2:22][C:23](=[O:26])[CH2:24][CH3:25]>CN(C)C=O>[CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:4][CH2:5][CH:22]([C:23](=[O:26])[CH2:24][CH3:25])[C:21](=[O:27])[CH3:20])[CH3:2]
Reactant: CCC(=CCCc1ccc2c(c1)OCO2)CCI
Reactant: CCC(=O)CC(C)=O
Agent: [Li]
Solvent: CN(C)C=O
Product: CCC(=O)C(CCC(=CCCc1ccc2c(c1)OCO2)CC)C(C)=O

Procedure:
[I; Ar is 3,4-methylenedioxyphenyl, R0 is H, R' is CH3CO, R" is CH3CH2CO, Y is C(C2H5)=CHCH2CH2 ] was prepared from 23.2 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) and 22.3 g. of the lithium salt of 2,4-hexanedione (prepared by the procedure described in Example 8 below) in 300 ml. of dimethylformamide according to the procedure described above in Example 2. There was thus obtained 21 g. of crude product which was chromatographed on 600 g. of silica gel in pentane solution containing 20% benzene. The column was eluted with the pentane-benzene-ether solvent series. Benzene containing 3% ether brought out the desired product, 14.5 g. of 3-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-2,4-hexanedione as a yellow oil.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][NH:9][C:10](=[O:12])[CH3:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[S:4]
Reactant: CC(=O)NCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)NCC(=NNC(N)=S)c1ccccc1
Yield: 78 %

Procedure:
Thiosemicarbazide (1.98 g, 20 mmol) was added to a solution of N-(2-oxo-2-phenyl-ethyl)-acetamide (3.84 g, 20 mmol, prepared in the previous step, in 70 ml of methanol plus 5.4 ml of 1N HCl plus 5.0 ml of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration and dried to give 3.9 g (78%) of the title compound as a white solid, mp 208-211° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:4].[CH2:16]([P:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C(OCC)(=O)C>[Cl-:1].[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:3](=[O:4])[CH2:2][P+:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(OC(=O)CCl)cc1
Reactant: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Product: CCCC[P+](CCCC)(CCCC)CC(=O)Oc1ccc(NC(C)=O)cc1
Product: [Cl-]
Temperature: 25 °C
Yield: 65 %

Procedure:
4-Acetamidophenyl 2-chloroacetate [2] (1.138 g, 5 mmol) and tributylphosphine (0.475 g, 6 mmol) were suspended in 50 ml of anhydrous ethyl acetate and refluxed for 48 hrs. After cooling to room temperature the white precipitate was filtered, washed with ethylacetate and diethylether and dried under reduced pressure to give [6]. The crude product was crystallized twice from acetonitrile to give pure [6] in 65% yield. Identity and purity was confirmed via 1H and 13C NMR. The desired compound is isolated as colourless needles. 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=10.49 (s, 1H), 7.71 (d, J=8.95 Hz, 2H), 7.12 (d, J=8.95 Hz, 2H), 4.18 (d, J=14.33, 2H), 2.41 (m, 3H), 2.06 (s, 3H), 1.55 (m, 6H), 1.41 (m, 6H), 0.91 (t, J=7.17). 31P-NMR (121.5 MHz, d6-DMSO) δ(ppm)=34.8. 13C-NMR (75 MHz, d6-DMSO) δ(ppm)=168.4, 164.7, 144.8, 137.8, 121.4, 119.9, 25.8 (d, J=47.9 Hz), 23.9, 23.3 (d, J=16.77 Hz), 22.6 (d, J=4.43 Hz), 18.2 (d, J=47.7 Hz), 13.2. mp 199° C. (dec), T5%onset 197° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([Cl:24])[CH:8]=1)(=O)=O.[C-:25]#[N:26].[Na+]>CN(C)C=O.C(OCC)C>[Cl:24][C:9]1[CH:8]=[C:7]([CH2:6][C:25]#[N:26])[C:15]2[C:11](=[CH:12][N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=1
Reactant: [C-]#N
Reactant: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(COS(C)(=O)=O)c2n1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc2cc(Cl)cc(CC#N)c2n1
Reaction time: 0.5 h

Procedure:
To a solution of (5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methyl methanesulfonate (3.25 g, 8.3 mmol) in dimethylformamide (10 mL) at room temperature was added sodium cyanide (0.815 g, 16.6 mmol). The reaction was placed in a 60° C. oil bath and allowed to stir for 30 min. The reaction was cooled, diluted with diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 2.33 g (87%). 1H-NMR (CDCl3, 500 MHz) δ 8.07 (s, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.32 (d, J=1.2 Hz, 1H), 5.68 (s, 2H), 4.09 (s, 2H), 3.62 (t, J=8.2 Hz, 2H), 0.93 (t, J=7.9 Hz, 2H), -0.04 (s, 9H), 13C NMR (126 MHz, CDCl3) δ ppm 145.7, 127.7, 126.4, 123.2, 122.4, 121.8, 119.5, 117.0, 82.1, 67.9, 19.4, 17.9, −1.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Cl)=[CH:4][C:3]=1[Cl:12].[BH4-].[Na+].C[O-].[Na+].CC(OC)(C)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][O:11]2)=[CH:4][C:3]=1[Cl:12]
Reactant: O=C(CCl)c1ccc(Br)c(Cl)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCO
Product: Clc1cc(C2CO2)ccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
To a stirred solution of 1-(4-bromo-3-chlorophenyl)-2-chloroethanone (18.4 g) in ethanol (200 ml) at 5° C. was added portionwise over 5 min NaBH4 (2.23 g). The reaction mixture was then stirred at room temperature for 90 min to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (1.59 g) was then added and the reaction mixture was stirred at 50° C. for 4 h. TLC analysis showed the reaction was complete. The reaction mixture was then poured into TBME and extracted with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-(4-bromo-3-chlorophenyl)oxirane (15.2 g) as a brown oil which was used in the next step without further purification.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][CH3:17])[N:13]=[CH:12][N:11]=2)[CH:5]=1.ClC1N=CN=C(C2C=[C:28](C=CC=2)[C:29]([OH:31])=[O:30])C=1>CN>[C:4]([O:31][C:29](=[O:30])[CH2:28][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][CH3:17])[N:13]=[CH:12][N:11]=2)[CH:5]=1)=[O:18])([CH3:9])([CH3:5])[CH3:3]
Reactant: O=C(O)c1cccc(-c2cc(Cl)ncn2)c1
Reactant: CNc1cc(-c2cccc(C(=O)OC)c2)ncn1
Agent: CN
Product: CNc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Temperature: 50 °C
Reaction time: 36 h

Procedure:
The title compound was prepared from 3-[6-methylamino-pyrimidin-4-yl]-benzoic acid methyl ester [prepared by the following procedure: 3-(6-Chloro-pyrimidin-4-yl)-benzoic acid (1.49 g, 6 mmol) was heated in 40% aqueous methylamine (5 ml) to 80° C. for 14 h. The mixture was evaporated in vacuum and the residual oil was stirred in 1N HCl-MeOH (10 ml) for 36 h at 50° C. The crude product was purified by chromatography (silica gel, AcOEt) to give the methyl ester as yellow solid (0.62 g).] (0.60 g, 2.4 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a white solid (0.72 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:5]2[C:6](=[O:10])[C:7]=1[CH2:8][CH3:9].[CH3:16]I.[BH4-].[Na+].[ClH:20]>C(O)C.O.CC(C)=O>[ClH:20].[CH3:16][N:3]1[CH:2]([CH3:1])[CH:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]2[CH:11]([CH3:15])[CH2:12][CH2:13][CH2:14][CH:4]12
Reactant: CCc1c(C)nc2cccc(C)n2c1=O
Reactant: CI
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CCC1C(=O)N2C(C)CCCC2N(C)C1C
Reaction time: 24 h
Yield: 41 %

Procedure:
0.01 moles of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine are dissolved in 20 ml. of acetone, 0.03 moles of methyl iodide are added and the mixture is kept in a bomb tube at 150° C. for 24 hours. The solution is evaporated to dryness, the residue is dissolved in 15 ml. of methanol and a solution of 0.05 moles of sodium tetrahydroborate (III) in 10 ml. of water is added. After 4 hours the methanol is distilled off and the aqueous phase is extracted with three 20-ml. portions of chloroform. The organic phase is dried, evaporated and added to the oily substance obtained are 10 ml. of ethanol saturated with hydrochloric acid. 1,2,6-trimethyl-3-ethyl-1,2,3,6,7,8,9,9a-octahydro-4-oxo-4H-pyrido[1,2-a]pyrimidine hydrochloride is obtained, which crystallizes when triturated with ether. The product obtained after recrystallization from a mixture of acetone and ether sublimates over 206° C. Yield: 41%.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](=[O:6])[CH3:5].O.[N+:9]([CH:12]([CH:15]=O)[CH:13]=O)([O-:11])=[O:10].[Na].[OH-].[Na+]>C(O)C.O>[CH:2]([C:3]1[CH:15]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=[CH:5][C:4]=1[OH:6])([CH3:7])[CH3:1]
Reactant: CC(=O)CC(C)C
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-Methyl-2-pentanone (4.85 g, 48 mmol) in 40 mL of ethanol was added dropwise to a solution of sodium nitromalonaldehyde monohydrate (7.61 g, 48 mmol) in 40 mL of water. NaOH (48 ml of 1N aqueous solution) was then added to the reaction mixture. The mixture was stirred at room temperature overnight, and solvent was removed under reduced pressure. The residue was diluted with water and neutralized, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography with silica eluting with 15% ethyl acetate in hexanes to yield 4.7 g of 2-isopropyl-4-nitrophenol.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:19].[CH2:20]([O:27][CH2:28][C@@H:29]([NH:33][C:34](=[O:46])[C:35]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([CH3:37])[CH3:36])[C:30](O)=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC#N.O>[CH2:20]([O:27][CH2:28][C@@H:29]([NH:33][C:34](=[O:46])[C:35]([NH:38][C:39](=[O:40])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:37])[CH3:36])[C:30]([N:15]1[CH2:16][CH2:17][CH2:18][C:4]2([C:3](=[O:19])[N:2]([CH3:1])[CH2:6][CH:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH2:14]1)=[O:31])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: CN1CC(c2ccccc2)C2(CCCNCC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC2)C1=O
Reaction time: 0.08 h

Procedure:
A diastereomeric mixture. of 2-methyl-4-phenyl-2,8-diazaspiro[4.6]undecan-1-one (200 mg; 0.774 mmol) in MeCN (2.58 ml) was treated with (R)-3-(benzyloxy)-2-(2-(tert-butoxy carbonylamino)-2-methyl propanamido) propanoic acid (Intermediate 3A) (295 mg; 0.774 mmol) followed by DIPEA (541 ul; 3.10 mmol). After stirring for 5 minutes, ®T3P (amide coupling agent 50% in DMF, 904 ul, 1.548 mmol) was added and the mixture was stirred at RT overnight. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 50-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:7].[C:18]1([CH2:24][S:25](Cl)(=[O:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[C:18]1([CH2:24][S:25]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[C:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:7])(=[O:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: O=C(OCCCc1cccnc1)C1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCc1cccnc1)[C@@H]1CCCN1S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A solution of 3-(3-Pyridyl)-1-propyl pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and a-toluenesulfonyl chloride (160 mg; 0.9 mmol) in methylene chloride (20 mL) was treated with triethylamine (90 mg; 0.9 mmol) and stirred for 2 hours at room temperature. The reaction mixture was filtered to remove solids and applied directly to a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 150 mg (43%) of Compound 4 (Table I) as a clear oil. 1H NMR (300 MHz, CDCl3): δ 1.81-1.85 (m, 2H) ; 1.95-2.02 (m, 3H) ; 2.10-2.25 (m, 1H); 2.69-2.74 (t, 2H); 2.85-2.97 (m, 1H); 3.24-3.27 (m, 1H); 4.16-4.20 (m, 2H); 4.29 (d, 1H); 4.34 (m, 1H); 4.45 (d, 1H); 7.20-7.25 (m, 1H); 7.35 (m, 3H); 7.49-7.52 (m, 3H); 8.46 (s, 2H). Analysis calculated for C20H24N2O3S: C, 61.83; H, 6.23; N, 7.21. Found: C, 61.59; H, 6.24; N, 7.17.
Reaction SMILES: [C-]#N.[K+].C(=O)C1C=CC=CC=1.S1C=CC=C1[C:17]([C:25]([C:27]([OH:39])([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)C1C=CC=CC=1)=O)(O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20]C=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].[NH:45]1[CH2:51][CH2:50][CH2:49][CH2:48][NH:47][C:46]1=[S:52]>CC(C)=O.C(O)C>[CH3:40][S:41]([O:39][C:27]1([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)[N:47]2[CH2:48][CH2:49][CH2:50][CH2:51][N:45]=[C:46]2[S:52][CH:25]1[C:17]1[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:43])=[O:42]
Reactant: S=C1NCCCCN1
Reactant: O=C(C(O)(c1ccccc1)c1cccs1)C(O)(c1ccccc1)c1cccs1
Reactant: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: CS(=O)(=O)OC1(c2cccs2)C(c2ccccc2)SC2=NCCCCN21
Reaction time: 48 h

Procedure:
A mixture of 9.2 ml. of thiophene-2-carboxyaldehyde, 8 g. of potassium cyanide and 10.1 ml. of benzaldehyde in 100 ml. of 65% ethanol is reacted as described in Example 20, giving 6.2 g. of 2-thienyl-α-hydroxybenzyl ketone. A 4.36 g. portion of this ketone is reacted with methanesulfonyl chloride as described in Example 20, giving 3.2 g. of the methanesulfonate ester. A 2.64 g. portion of this ester and 1.30 g. of hexahydro-2H-1,3-diazepine-2-thione in 100 ml. of acetone are allowed to stand 48 hours, the solid is collected, washed with ether and dried in vacuo, giving 2.8 g. of the desired product, m.p. 149°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:20]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: BrCc1cccnc1
Agent: Br
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1cccnc1

Procedure:
The title compound, MS: m/e=309.3 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: S1CCC([C:7]2[CH:12]=[C:11]([N:13]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:10]3[N:30]=[CH:31][CH:32]=[C:9]3[N:8]=2)CC1.C1C=C(Cl)C=C(C(OO)=O)C=1>>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:23][CH2:22][N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:11]1[N:10]2[N:30]=[CH:31][CH:32]=[C:9]2[N:8]=[CH:7][CH:12]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCSCC2)nc2ccnn12
Agent: O=C(OO)c1cccc(Cl)c1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1ccnc2ccnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound, 5-(tetrahydro-2H-thiopyran-4-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (18.7 mmol, 9.23 g) DCM (100 mL) was added mCPBA and stirred at rt for 1 h. The reaction was quenched with Na2S2O3 (aq.) and diluted with DCM (100 mL). The separated organic layer was washed with NaHCO3 (2*) and brine, dried over Na2SO4, and concentrated to afford crude compound, 5-(tetrahydro-2H-thiopyran-4-yl-1′,1′-dioxide)-)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine as a purple oil, which was used without further purification. HPLC-MS TR=2.72 min (UV 254 nm, 5 min method); mass calculated for formula C23H42N4O4SSi2 526.2, observed LCMS m/z 527.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[O:11]([NH2:13])[CH3:12]>>[CH3:12][O:11][N:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1]
Reactant: O=Cc1ccccc1F
Reactant: CON
Agent: Cl
Product: CON=Cc1ccccc1F
Yield: 98 %

Procedure:
Reaction of 2-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (98% yield). HPLC indicated a 91:9 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.99 (3H, s, OCH3), 7.07 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.34 (1H, m, aromatic), 7.82 (1H, m, aromatic), 8.31 (1H, s, CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=4)[CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:37].O>O1CCOCC1>[CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[C:7](=[O:37])[C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[CH:22]=4)[CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cc(OC)c(OC)cc3C1)CC2
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CC(N(C)CCCN1CCc3cc(OC)c(OC)cc3C(=O)C1=O)CC2

Procedure:
Here, 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(6,7-dimethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (1.64 g, 0.0034 mol) is added at 70° C. to a suspension of selenium dioxide (0.41 g, 0.0036 mol) and Celite (0.34 g) in 1,4-dioxan (17 ml) and water (0.68 ml) is added and the mixture is refluxed for 40 hours. After cooling, it is suction filtered, concentrated by rotary evaporation in vacuo and purified over silica gel (40 g) (32-63 μm) with methylene chloride and increasing amounts of ethanol (up to 40%). The clean fractions are concentrated by evaporation and the hydrochloride is precipitated from acetone. Yield: 0.6 g. Mp: >145° C. (decomp.).