Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].[Cl-].[Li+]>C(N(CC)CC)C.CN(C)C=O.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(Cl)cc1I
Agent: I[Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(Cl)cnc1N
Temperature: 40 °C

Procedure:
A suspension of 2.54 g of 5-chloro-3-iodopyridin-2-ylamine, 2.12 ml of ethynyltrimethylsilane, 0.38 g of copper iodide and 0.47 g of lithium chloride in 7 ml of triethylamine and 75 ml of dimethylformamide is degassed under argon for approximately 15 minutes. 0.408 g of [1,1′-bis(diphenylphosphino)ferrocene] palladium(II) chloride is added to the above suspension. The mixture is heated at around 40° C. for approximately 19 hours and then concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 50 ml of water, and extracted with three times 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. 1.63 g of 5-chloro-3-trimethylsilanylethynylpyridin-2-ylamine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH:20]4[CH:15]([CH2:16][CH2:17][NH:18][CH2:19]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[C:37]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:38]([C:43](O)=[O:44])=[CH:39][CH:40]=[CH:41][CH:42]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[C:37]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([N:18]1[CH2:17][CH2:16][CH:15]2[CH:20]([N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:19]1)=[O:44]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: c1ccc(-c2ccnc(N3CC4CCNCC43)n2)cc1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1ccccc1-c1ccccc1)N1CCC2CN(c3nccc(-c4ccccc4)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 8-(4-phenyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 6) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and biphenyl-2-carboxylic acid for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C29H26N4O, 446.54; m/z found, 447.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.44-7.28 (m, 13H), 7.27-6.79 (m, 3H), 4.70-3.66 (m, 4H), 3.59-2.31 (m, 3H), 2.19-0.93 (M, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-bromophenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 21, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH:8]=[N:9]O)[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ON=Cc1cc(O)ncn1
Solvent: CN(C)c1ccccc1
Product: N#Cc1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Hydroxy-pyrimidine-4-carbaldehyde oxime (9.3 g, 67 mmol) was stirred in 37 ml POCl3 under N2 at 40° C. for 30 min, 60° C. for 30 min, and 80° C. for one h. N,N,-Dimethylaniline was added very slowly by syringe, and stirredfor one h at 80° C. After cooling to 0° C., the mixture was poured into a separatory funnel containing 300 g of ice. The mixture was carefully swirled, then extracted with 500 ml t-BuOMe. The organic layer was washed with 1 N HCl (4×100 ml), then several times with NaHCO3, then brine. Acidic and basic aqueous layers were separately back-extracted with t-BuOMe, and the organics again washed with 1 N HCl, saturated aqueous NaHCO3, and brine. The combined organic layers were dried with Na2SO4 and concentrated by rotary evaporator. The residue was filtered through a pad of silica gel, applying in CH2Cl2 and eluting with 10:1 hexanes/t-BuOMe. Fractions were carefully concentrated to obtain 6-chloro-pyrimidine-4-carbonitrile as a (volatile) pale yellow, semi-crystalline solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12]Cl)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][C:15]([NH2:17])=[S:16].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.O>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:14]=[C:15]([NH2:17])[S:16][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(=NOC)c1csc(N)n1
Reaction time: 0.58 h
Yield: 68.5 %

Procedure:
Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (50 g.) was added over 3 minutes with stirred at ambient temperature to a solution of thiourea (18.4 g.) and sodium acetate (19.8 g.) in a mixture of methanol (250 ml.) and water (250 ml.). After stirring for 35 minutes at 40° to 45° C., the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated aqueous solution of sodium bicarbonate. After stirring for 30 minutes at the same temperature, precipitates were collected by filtration, washed with water (200 ml.) and then with diisopropyl ether (100 ml.), and dried to give colorless crystals of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (37.8 g.), m.p. 161° to 162° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[C:5]([OH:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:9])=[C:13]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[O:11][C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)c1nc(Br)ccc1O
Reactant: O=C(CBr)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2ccc(Br)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a mixture of 1-(6-bromo-3-hydroxypyridin-2-yl)ethanone (1.64 g) synthesized above, 2-bromo-1-cyclohexylethanone (2.34 g) synthesized in Example A51(1) and N,N-dimethylformamide (20 mL) was added potassium carbonate (3.15 g), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (865 mg, 35%) as a white solid.
Reaction SMILES: N.[NH2-].[Na+].[C:4]1([S:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)[C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28]I.Cl>C(OCC)C.O>[C:4]1([S:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)([CH3:28])[C:12]([OH:14])=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C(Sc1ccccc1)c1cccc(Oc2ccccc2)c1
Reactant: CI
Agent: Cl
Agent: N
Agent: [NH2-]
Solvent: CCOCC
Solvent: O
Product: CC(Sc1ccccc1)(C(=O)O)c1cccc(Oc2ccccc2)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
15 ml of liquid ammonia was charged into a 50 ml flask and 0.2 g (8.7 mmols) of sodium metal was dissolved therein in the presence of a catalytic amount of ferric nitrate thereby forming a liquid ammonia suspension of sodium amide. Thereafter, 1.22 g (3.63 mmols) of 2-phenylthio-2-(3-phenoxyphenyl)acetic acid prepared as described in Example 1 dissolved in 10 ml of diethyl ether was added dropwise to the above suspension of sodium amide. The reaction mixture was then stirred for 30 minutes at a temperature of -40° C. and a solution of 0.75 g (5.3 mmols) of methyl iodide in 5 ml of diethyl ether was added to the reaction mixture which was then stirred for further 30 minutes at -40° C. The reaction mixture was then allowed to warm slowly by removing the cooling bath used and finally heated while refluxing for 15 minutes to complete the reaction. 30 ml of water was added to the reaction mixture to dissolve any solid substances and the mixture was rendered acidic with 1 N hydrochloric acid followed by being extracted with diethyl ether. The etherial extract was dried over anhydrous sodium sulfate and concentrated to obtain 1.23 g of a crude 2-phenylthio-2-(3-phenoxyphenyl)propionic acid. The resulting crude product was then purified by silica gel column chromatography eluting with diethyl ether-hexane (1:5 by volume) to obtain 1.10 g (87% yield) of the above product in a substantially pure form.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[Na+].[C:9](#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)Cl>CN(C)C=O.O>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5]
Reactant: CSCS(C)=O
Reactant: N#Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CSC(=C(N)c1ccccc1)S(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
1.815 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of dimethylformamide, and the solution was added with 380 mg of sodium hydride under cooling with ice, and then stirred for 1.5 hours at room temperature. Thereafter, upon addition of 1.515g of benzonitrile, the mixture was stirred for 1.5 hours at room temperature and for 10 hours at 50° C., followed by addition of 70 ml of methylene chloride and 2 ml of water and stirring for 20 minutes at room temperature. After drying with Glauber's salt and filtration, the filtrate was concentrated under reduced pressure. The resulting product was crystallized from methylene chloride-carbon tetrachloride-cyclohexane to obtain 2.332 g of 1-methylsulfinyl-1-methylthio-2-amino-2-phenylethylene. The isolation yield was 70%.
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[NH2:27]>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:33]3[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:26]([NH2:27])=[O:28])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(C(N)=O)c2)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-carbamoylphenylboronic acid in a manner analogous to Example 269. MS (M+H)+ 485.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C:13]12[CH2:20][CH2:19][C:16]([C:21]([OH:23])=[O:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)[CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)Cl.CO>[CH2:8]([C:13]12[CH2:18][CH2:17][C:16]([C:21]([O:23][CH3:1])=[O:22])([CH2:15][CH2:14]1)[CH2:19][CH2:20]2)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC12CCC(C(=O)O)(CC1)CC2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: CCCCCC12CCC(C(=O)OC)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(Trimethylsilyl)diazomethane (2M/hexane, 53 mL, 106 mmol) was added slowly to a solution of 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid (2-A) (20.3 g, 90.6 mmol) in methylene chloride (100 mL) and methanol (40 mL) until the yellow color persisted. After stirring for 10 min at room temperature, the solution was concentrated in vacuo to give methyl 4-pentylbicyclo[2.2.2]octane-1-carboxylate (2-B). 1H NMR (500 MHz, CDCl3): δ 0.89 (t, 3H); 1.20 (m, 8H); 1.39 (m, 6H); 1.77 (m, 6H); 3.65 (s, 3H) ppm.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH3:18])[C:6]=1[Cl:19].[NH4+:21].[OH-]>>[Cl:19][C:6]1[C:7]([CH3:18])=[CH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:10][C:5]=1[CH2:4][C:3]([NH2:21])=[O:2]
Reactant: [NH4+]
Reactant: COC(=O)Cc1cc(N2CCN(C)CC2)cc(C)c1Cl
Agent: [OH-]
Product: Cc1cc(N2CCN(C)CC2)cc(CC(N)=O)c1Cl
Temperature: 25 °C

Procedure:
(5Bromo-2-chloro-3-methyl-phenyl)-acetic acid methyl ester (2.0 g, 7.2 mmol), N-methylpiperazine (960 μL, 8.6 mmol) and Cs2CO3 (3.3 g, 10.1 mmol) are suspended in toluene (80 mL). Pd(OAc)2 (81 mg, 0.36 mmol) and BINAP (224 mg, 0.36 mmol) are added and the reaction is stirred at 100° C. overnight. The mixture is filtered through Celite and the solvent is evaporated. The residue is purified by FCC (AcOEt/AcOH/H2O 60:15:15) to afford 2-[2-chloro-3-methyl-5(4-methyl-piperazin-1-yl)-phenyl]-acetic acid methyl ester. The ester is suspended in NH4OH 25% (60 mL). The mixture is stirred ovemight at RT and the precipitate is filtered off to yield the amide. 1H NMR (DMSO, 400 MHz) δ 2.20 (s, 3H), 2.27 (s, 3H), 2.40-2.45 (m, 4H), 3.07-3.13 (m, 4H), 3.48 (s, 2H), 6.78 (s, 1H), 6.82 (s, 1H), 6.91 (br s, 1H), 7.34 (br s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[N:29]>CN(C)C=O>[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:3][C:4]1[CH:5]=[C:6]([O:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1)#[N:29]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: N#CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCCCCC#N)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
Sodium hydride (24 mg, 1 mmol; 100%) was added to solution of 250 mg (0.855 mmol) of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester, as prepared in step (c) of Example 1, in 2 mL of N,N-dimethylformamide. After 5 min, 130 μL (0.93 mmol) of 6-bromohexanenitrile was added to the reaction mixture. The reaction mixture was stirred for 2 h at ambient temperature, quenched with brine ( 50 mL), extracted into diethyl ether (50 mL), washed with water (3×10 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (methylene chloride/petroleum ether 4:1 to 100:0) to give 250 mg of the title compound as a colorless oil which solidified upon standing. 1H-NMR (300 MHz, CDCl3) δ 7.97 (dd, 1 H, J=1.4, 7.8 Hz), 7.56-7.65 (m, 2 H), 7.36-7.41 (m, 1 H), 6.59 (br s, 1 H), 6.53 (br, s 1 H), 6.48 (t, 1 H, J=1.1 Hz), 3.85 (t, 2 H), 2.38 (t, 2 H), 2.24 (s, 3 H), and 1.6-1.8 (m, 6 H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C19H20NClO4S: 416.1 (M+Na). Found: 416.1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:51][C:52]1[N:57]=[CH:56][N:55]=[C:54]2[N:58]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[Cl:67])[N:59]=[CH:60][C:53]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[Cl:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[N:58]1[C:54]2=[N:55][CH:56]=[N:57][C:52]([O:51][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[O:43])=[C:53]2[CH:60]=[N:59]1
Reactant: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccccn1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccccn1)[C@H](COCCO)Oc1ncnc2c1cnn2-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (0.984 mL, 0.98 mmol) was added in one portion to a stirred solution of (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(pyridin-2-yl)propanamide (Intermediate AQ5) (0.682 g, 0.98 mmol) in tetrahydrofuran (15 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated NH4Cl (10 mL), and diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (50 mL), The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane to afford the product (0.335 g, 74.9%). 1H NMR: (400 MHz, CDCl3) δ 2.91 (1H, s), 3.74-3.79 (4H, m), 4.15-4.25 (2H, m), 6.10 (1H, t), 7.06-7.10 (1H, m), 7.45-7.63 (4H, m), 7.71-7.75 (1H, m), 8.19 (1H, d), 8.27-8.29 (1H, m), 8.44 (1H, s), 8.60 (1H, s), 9.01 (1H, s); m/z (ES+) (M+H)+=455; HPLC tR=1.76 min.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[O:7][CH2:8][CH2:9][S:10][CH:11]=1)[C:3]([OH:5])=[O:4].[C:12]([O:16][C:17](N=[N+]=[N-])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C=O>[C:12]([O:16][C:17]([NH:1][CH:2]([C:6]1[O:7][CH2:8][CH2:9][S:10][CH:11]=1)[C:3]([OH:5])=[O:4])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NC(C(=O)O)C1=CSCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1=CSCCO1
Temperature: 35 °C
Reaction time: 48 h
Yield: 65.6 %

Procedure:
DL-α-Amino-(5,6-dihydro-1,4-oxathiin-2-yl)-acetic acid (25.4 g.) is suspended in dimethylformamide (435 cc.); tert.-butoxycarbonyl azide (41.5 g.) and triethylamine (51 cc.) are added. The reagents are left in contact for 48 hours whilst stirring at a temperature of 35° C. The solution is concentrated under reduced pressure (1 mm Hg), the residue is taken up in water (300 cc.), and the pH is adjusted to 8.5 by adding a saturated sodium bicarbonate solution. The aqueous phase is extracted twice with ethyl ether (a total of 500 cc.) which is discarded, and is then acidified to pH = 3 by adding 4 N hydrochloric acid A product precipitates, which is filtered off and then dissolved in methylene chloride (600 cc.). The solution obtained is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg). DL-α-Tert.-butoxycarbonylamino-(5,6-dihydro-1,4-oxathiin-2-yl)-acetic acid (26.2 g.), melting at 160° C is thus obtained.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.[Br:16][C:17]1[N:21]2[CH:22]=[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:24]([C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)=[N:25][C:20]2=[N:19][C:18]=1[CH3:40].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[Br:16][C:17]1[N:21]2[CH:22]=[C:23]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:32][CH:33]=3)=[N:25][C:20]2=[N:19][C:18]=1[CH3:40]
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2c1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nc2nc(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)c(-c3ccccc3)cn2c1Br
Reaction time: 1 h

Procedure:
147.6 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl (intermediate example 44.0) are dissolved in 4.3 ml NMP. After addition of 0.16 ml triethylamine the reaction mixture is stirred for one hour. 192 mg (0.49 mmol) 4-(3-Bromo-2-methyl-6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde and 0.05 mL acetic acid are added and the reaction mixture is stirred for 23 hours at room temperature. 114.1 mg (0.54 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for three days. The reaction mixture is treated with 30 mL saturated NaHCO3 and stirred for 45 minutes. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 3.5 mg (1.2%) of the desired product are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>C1(C)C=CC=CC=1.C(O)C>[C:2]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)C(Cc1cccc(Br)c1)CS(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)C(Cc1cccc(-c2ccccc2)c1)CS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
3-(3-Bromo-phenyl)-2-benzylsulfonylmethyl-propionic acid (0.5 g, 1.26 mmol) was dissolved in toluene (20 mL) and ethanol (5 mL). Tetrakistriphenylphosphine palladium (146 mg, 0.126 mmol) was added and the mixture was stirred at ambient temperature under nitrogen for 30 minutes. Powdered potassium carbonate (870 mg, 6.3 mmol) and phenylboronic acid (200 mg, 1.64 mmol) were added, and the reaction mixture was heated at 75° C. for 2 hours. After cooling, the mixture was acidified with 1N aqueous HCl and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried with magnesium sulfate and evaporated. The acid was purified by flash chromatography on silica gel (ethyl acetate/hexane; 1:1) to yield 3-biphenyl-3-yl-2-benzylsulfonylmethyl-propionic acid (0.40 g).
Reaction SMILES: FC1C(CN2C=CC(N)=N2)=CC=CN=1.[F:15][C:16]1[N:21]=[C:20]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([N:28]3C(=O)C4C(=CC=CC=4)C3=O)=[N:24]2)[CH:19]=[CH:18][CH:17]=1>>[F:15][C:16]1[N:21]=[C:20]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2cccc(F)n2)n1
Agent: Nc1ccn(Cc2cccnc2F)n1
Product: Nc1ccn(Cc2cccc(F)n2)n1
Yield: 89.6 %

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 47, replacing Intermediate 46 with Intermediate 45 (90 mg, 0.279 mmol) to yield the title compound (48 mg, 0.250 mmol, 48% yield). 1H NMR (300 MHz, CDCl3) δ ppm: 7.73 (q, 1H), 7.30 (d, 1H), 6.89 (dd, 1H), 6.83 (dd, 1H), 5.67 (d, 1H), 5.16 (s, 2H), 2.87 (br s, 2H). [ES+MS] m/z 192 (MH+).