Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]2[C:16]([NH2:17])=[N:15][CH:14]=[C:13]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH:20]=[CH:21][CH:22]=[N:23]4)[N:12]=2)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1N=C(N[C@@H](C2C=CC=CC=2)CC)C(N)=NC=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.[C:59](=O)([O-])[O-:60].[K+].[K+]>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.CN(C)C=O.O>[C:1]1([C@H:7]([N:10]2[C:11]3=[N:12][C:13]([C:18]4[CH:27]=[CH:26][CH:25]=[C:24]5[C:19]=4[CH:20]=[CH:21][CH:22]=[N:23]5)=[CH:14][N:15]=[C:16]3[NH:17][C:59]2=[O:60])[CH2:8][CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CC[C@@H](Nc1nc(-c2cccc3ncccc23)cnc1N)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[C@@H](Nc1nc(Br)cnc1N)c1ccccc1
Agent: OB(O)c1cccc2ncccc12
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)nc21
Yield: 93 %

Procedure:
(R)-N2-(1-phenylpropyl)-6-(quinolin-5-yl)pyrazine-2,3-diamine. (R)-6-Bromo-N2-(1-phenylpropyl)pyrazine-2,3-diamine (0.440 g, 1.43 mmol), quinoline-5-boronic acid (0.273 g, 1.58 mmol), tetrakis(triphenylphosphine)palladium (0.165 g, 0.143 mmol), potassium carbonate (0.789 g, 5.72 mmol), water (8 mL) and dimethylformamide (30 mL) were reacted according to General Procedure B. The crude was purified via Biotage silica gel chromatography (0-10% methanol/dichloromethane, 40S column) to afford the title compound (0.476 g, 93% yield). MS (ESI) m/z 356.4 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1C=CC=CC=1.O>[CH2:10]([NH:17][CH:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(C)CCCC(=O)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CCCC(NCc2ccccc2)C1
Temperature: 25 °C
Yield: 19.4 %

Procedure:
3,3-Dimethylcyclohexanone (3 g, 23.77 mmol) and benzylamine (2.73 mL, 24.96 mmol) were dissolved in benzene (20 mL) and stirred at reflux with continuous removal of H2O for 3 hours. The reaction mixture was allowed to cool to RT and the solvent was evaporated. The imine intermediate was dissolved in DCM (100 mL) and cooled to 0° C. Sodium triacetoxyborohydride (95%, 6.36 g, 28.53 mmol) and acetic acid (1.5 mL, 26.15 mmol) were added. After about 20 minutes the ice bath was removed, and the suspension stirred at RT overnight. The reaction mixture was cooled to 0° C. and saturated aqueous NaHCO3 was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed once more with saturated aqueous NaHCO3, dried (Na2SO4), filtered and evaporated. The remaining yellow oil (5 g) was purified by SiO2 chromatography (300 g SiO2, DCM/(DCM:MeOH:NH4OH 60:10:1) 100 to 87% DCM) to give 1 g of racemic benzyl-(3,3-dimethyl-cyclohexyl)-amine as a light yellow oil (19% yield).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C-]#N.[Na+].[CH3:27][NH:28]CCNC>C1(C)C=CC=CC=1.[Cu]I>[C:27]([C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)#[N:28]
Reactant: CC(C)OC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCC[C@H]1CNc1ccc2ncc(C#N)n2n1
Yield: 24.3 %

Procedure:
A solution of (S)-iso-propyl 2-(((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)pyrrolidine-1-carboxylate (300 mg, 0.79 mmol), NaCN (46 mg, 0.94 mmol), CuI (15 mg, 0.08 mmol), KI (27 mg, 0.16 mmol) and N1,N2-dimethylethane-1,2-diamine (0.085 mL, 0.79 mmol) in toluene (0.8 mL) was stirred at 110° C. for 12 h. The reaction was cooled, concentrated, taken up with EtOAc and water, extracted and dried organic layer with MgSO4. The organic layer was concentrated and purified by ISCO (0-5% MeOH/DCM), then following PREP HPLC (neutral) to give (S)-isopropyl 2-(((3-cyanoimidazo[1,2-b]pyridazin-6-yl)amino)methyl)pyrrolidine-1-carboxylate (63 mg, 25% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.00 (s, 1H), 7.72 (d, J=9.85 Hz, 1H), 6.91 (d, J=9.85 Hz, 1H), 4.20 (m, 1H), 3.38-3.61 (m, 4H), 1.97-2.05 (m, 4H), 1.16-1.25 (m, 6H); LRMS (ESI) m/e 329.2 [(M+H)+, calcd for C16H21N6O2 329.4].
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].[C:12]([CH2:15][C:16](=O)[CH3:17])(=O)[CH3:13].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:16]([CH3:17])=[CH:15][C:12]([CH3:13])=[N:11]1
Reactant: COc1ccccc1NN
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1-n1nc(C)cc1C

Procedure:
3.50 g of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 60 ml of ethanol, and 2.06 ml of acetyl acetone was added and heated at reflux for 1 hour. To the reaction mixture was added 150 ml of water, neutralized with saturated aqueous solution of sodium carbonate, and extracted with 150 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to yield 3.88 g of the title compound.
Reaction SMILES: CON(C)[C:4](=[O:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:16][Mg+].[Br-]>C1COCC1>[O:14]=[C:4]([CH3:16])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (4.36 g, 0.02 mol) in THF (50 mL) added MeMgBr (40 ml, 0.08 ol) at −78° C. The formed mixture was stirred overnight. The mixture was quenched with NH4Cl and extracted with EtOAc. The organic phase was separated, dried over anhydrous Na2SO4, concentrated and purified by column chromatography to give tert-butyl 2-oxopropylcarbamate (2.5 g, 72%). 1H NMR (400 MHz, CDCl3): δ=1.42 (s, 9H), 2.18 (s, 3H), 4.01 (s, 2H), 5.22 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=CC=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.OC1CCN(C(OCCCC)=O)C1>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH:3]3[CH2:4][CH2:9][NH:1][CH2:2]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: CCCCOC(=O)N1CCC(O)C1
Product: Clc1ccc2[nH]c3c(OC4CCNC4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is tent-butyl 3-hydroxypyrrolidine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.26 (br s, 2H), 8.35 (s, 1H), 8.06 (d, J=1.2 Hz, 2H), 7.39-7.29 (m, 4H), 5.11 (t, J=3.8 Hz, 1H), 3.60-3.50 (m, 1H), 3.34 (d, J=11.6 Hz, 1H), 3.20 (td, J=10.2, 4.0 Hz, 1H), 2.88 (dd, J=12.2, 3.2 Hz, 1H), 2.40-2.30 (m, 1H), 2.22-2.10 (m, 1H); MS (ESI) m/z 408.1 (M−H)−; MS (ESI) m/z 410.0 (M+H)+
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH:26]=1)[CH:24]=[O:25]>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH:26]=1)[C:24]([OH:11])=[O:25]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C=O)c2)c(OC)c(OC)c1OC
Reactant: OO
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
An aqueous solution (10 ml) of sodium dihydrogenphosphate (12.0 g, 0.100 mol), an aqueous solution (30 ml) of sodium chlorite (5.19 g, 0.0577 mol) and aqueous hydrogen peroxide (1.701 ml, 30%) were added to an acetonitrile solution (30 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (5.60 g, 0.0128 mol) and the resulting solution was stirred at room temperature for 5 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (5.20 g, 0.0115 mol, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=O)=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[C:14]1([C:20]2[CH:24]=[C:23]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([CH2:32][NH2:33])[CH2:28][CH2:27]3)[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:1][C:2]1[C:3]([C:11]([NH:33][CH2:32][CH:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:23]3[O:22][N:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:24]=3)[CH2:31][CH2:30]2)=[O:13])=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCOc1ccc(N)c(C(=O)O)n1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Product: CCOc1ccc(N)c(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)n1

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 282 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]=[C:10](COC3C=CC(Cl)=CC=3Cl)[O:11][C:7]=2[CH:6]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-].O.Cl>CSC.ClCCl>[O:11]1[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:23]=[CH:22][C:8]=2[N:9]=[CH:10]1
Reactant: COC(=O)c1ccc2nc(COc3ccc(Cl)cc3Cl)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: CSC
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc2ncoc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.2 %

Procedure:
To a solution of 2-(2,4-dichloro-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester (100 mg, 0.29 mmol) in dimethyl sulfide (8 ml) and dichloromethane (58 ml) was added aluminum bromide (1.24 g, 4.64 mmol). The reaction mixture was stirred at room temperature for 2.5 h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2:MeOH=4:1) to give 2-2,4-dichloro-phenoxymethyl)-benzoxazole-6-carboxylic acid as a white solid (59.15 mg mg, 61.2% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:15][C:16](C)([O-:18])[CH3:17].[K+].ClCC(=O)C>CS(C)=O>[C:16]([CH2:17][O:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:18])[CH3:15]
Reactant: COC(=O)c1sc2ccccc2c1O
Reactant: CC(C)(C)[O-]
Agent: CC(=O)CCl
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1sc2ccccc2c1OCC(C)=O

Procedure:
To a solution of 12.6 g. of the product of Example 1 and 8.1 g. of potassium t-butoxide in 100 ml. of dimethyl sulfoxide was added, dropwise with stirring, 15 ml. of chloroacetone. The mixture was treated and the product was recovered as shown in Example 2, except that the product was crystallized from ethanol-water. The product was 10.7 g. of 3-(acetlymethoxy)benzo[b]thiophene-2-carboxylic acid, methyl ester, m.p. 57°-58°C. It was identified by NMR analysis and elemental microanalysis as follows.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:7][C:8](=[O:10])N)[CH3:2].N(OC(C)(C)C)=[O:24]>C(#N)C>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:6][CH2:7][C:8]([OH:24])=[O:10])[CH3:2]
Reactant: CC(C)(C)ON=O
Reactant: CCOC(=O)C(CCC(N)=O)NC(=O)OCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C(CCC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A suspension of the amide (2) (38 g, 0.1233 mol) in anhydrous acetonitrile (400 ml) was stirred at reflux under nitrogen and t-butyl nitrite (35 ml, 3.17 equiv.) was added quickly. The reflux was continued for 2 hrs. After cooling, the solvent was removed in a rotary evaporator. The residue was taken in water (250 ml) and ethyl acetate (500 ml) and the biphasic mixture was stirred well while solid sodium bicarbonate was slowly added to pH=7.5. Phases were separated and the organic phase was washed with 10% sodium bicarbonate (200 ml). The combined aqueous extracts were washed with ethyl acetate (300 ml), made acidic with 6N hydrochloric acid and extracted with ethyl acetate (2×300 ml). The combined extracts were washed with water (150 ml), dried over sodium sulfate, stripped and the residue was dried in a vacuum oven (50° C.) to produce (3) (24.6 g, 64.7%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C@H:10]([CH2:34][C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([N:42](CC3C=CC=CC=3)C(OC(C)(C)C)=O)[N:36]=2)[CH2:9]1)=O)(C)(C)C>CCO.[OH-].[OH-].[Pd+2]>[CH3:41][C:39]1[CH:38]=[C:37]([NH2:42])[N:36]=[C:35]([CH2:34][CH:10]2[CH:11]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH2:12][NH:8][CH2:9]2)[CH:40]=1
Reactant: Cc1cc(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2OCCN(CCOc2cccc(F)c2)C(=O)OC(C)(C)C)nc(N(Cc2ccccc2)C(=O)OC(C)(C)C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N)nc(CC2CNCC2OCCNCCOc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of 17a (30 mg, 39 μmol) in EtOH (5.0 mL) was added a 1:1 mixture of EtOH/concentrated HCl (10 mL) and Pd(OH)2/C (20%, 30 mg). The mixture was charged with H2 under the pressure of 500 psi. The reaction mixture was allowed to stir at room temperature for 40 h. The catalyst was removed by filtration through Celite, and the resulting Celite cake was washed with EtOH (4×3 mL) and 2 N HCl (3 mL). The combined filtrates were concentrated to yield inhibitor 2a, a yellow solid, as a hydrochloride salt (15 mg, 85%): 1H NMR (500 MHz, D2O) δ 2.08 (s, 3H), 2.60-2.63 (m, 2H), 2.70-2.80 (m, 1H), 2.97-3.03 (m, 1H), 3.13-3.16 (m, 1H), 3.17-3.37 (m, 3H), 3.38-3.50 (m, 3H), 3.54 (br s, 1H), 3.73 (br s, 1H), 4.05 (br s, 1H), 4.17 (br s, 2H), 6.33 (s, 1H), 6.44 (s, 1H), 6.50-6.55 (br s, 1H), 6.58-6.70 (m, 3H), 7.06-7.08 (m, 1H); 13C NMR (125 MHz, D2O) δ 21.3, 29.4, 41.7, 46.6, 47.0, 47.3, 49.5, 63.0, 64.0, 78.6, 108.4, 108.6, 108.7, 110.4, 110.5, 114.3, 130.9, 131.0, 145.8, 154.0, 158.3, 158.7, 158.8, 162.4, 164.4; LCQ-MS (M+H+) calcd for C21H30FN4O2 389. found 389; LC-TOF (M+H+) calcd for C21H30FN4O2 389.23473. found 389.23444.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[CH3:9][CH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[CH3:9][CH:10]1[CH2:15][CH2:14][C:13]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:12][CH2:11]1
Reactant: C#Cc1ccccn1
Reactant: CC1CCC(=O)CC1
Product: CC1CC=C(C#Cc2ccccn2)CC1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), 4-methylcyclohexanone (6.0 mmol, 672 mg); yields 2-[(4-methyl-1-cyclohexen-1-yl)ethynyl]pyridine as a transparent oil (250 mg, 21% overall yield). 1H NMR (CDCl3, 300 MHz) δ 8.57 (m, 1H), 7.59 (m, 1H), 7.39 (m, 1H), 7.20 (m, 1H), 6.30 (m, 1H), 2.22 (m, 3H), 1.72 (m, 3H), 1.25 (m, 1H), 0.99 (m, 3H). MS (EI ionization) 197 (M+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:45]([CH3:46])[N:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:41]2[N:45]([CH3:46])[N:44]=[CH:43][N:42]=2)=[O:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ncnn1C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3ncnn3C)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N,1-dimethyl-1H-1,2,4-triazole-5-carboxamide (Intermediate 49).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[Br:11])[CH:2]=[CH2:3].[C:13]([O-:16])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[Br:11])[O:12][C:5]1[CH:6]=[CH:7][C:8]([CH:13]=[O:16])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(O)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOc1cc(Oc2ccc(C=O)cc2)ccc1Br
Temperature: 100 °C
Yield: 166.3 %

Procedure:
4-Flurorbenzaldehyde (1.15 mL, 10.76 mmoles) was added to a solution of the product from Example 63B (1.76 g, 7.69 mmoles) and K2CO3 (3.19 g, 23.1 mmoles) in DMF (7.7 mL). The reaction mixture was heated to 100° C. for 14 h and was cooled to room temperature The crude products were diluted with diethyl ether, extracted with sat. NH4Cl, extracted with H2O (2×), rinsed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography on a prepacked Biotage colum (hexane to 4:1 hexane:ethyl acetate) on silica gel to provide the title compound (2.13 g, 83%) as a white solid.
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:9].[Si:20]([O:27][CH2:28][C@@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][NH:31][CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:27][CH2:28][C@@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][N:31]([CH:7]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:2]2)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: COc1ccc(COC(=O)CC2CCCC2O)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Product: COc1ccc(COC(=O)C(C2CCCC2)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccccc3)C2)cc1

Procedure:
The title compound was prepared from 233 mg (0.88 mol) of (R/S)-2-hydroxy-cyclopentylacetic acid, 4-(methoxy)benzyl ester (from EXAMPLE 15, Step B) and 209 mg (0.71 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) using a procedure analogous to that described in EXAMPLE 1, Step G to provide 326 mg (84%) of the title compounds as a mixture of diastereomers: RF: 0.64 (4:1 v/v hexanes/EtOAc); 1H NMR (300 Hz) δ 0.0 (2 s, 6H), 0.84, 0.85 (2 s, 9H), 1.18 (m, 11H), 1.42-1.82 (m, 7H), 2.23-2.34 (m, 2H), 2.65-3.18 (m, 6H), 3.43-3.59 (m, 2H), 3.81 (s, 3H), 5.01-5.19 (m, 2H), 6.85-6.91 (m, 2H), 7.14-7.36 (m, 7H).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:14]CCC.CI>C1COCC1>[C:1]([NH:5][S:6]([C:9]1([CH3:14])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of N-tert-butyl-(3-chloro)propylsulfonamide (4.3 g, 20 mmol) was dissolved in dry THF (100 mL) and cooled to −78° C. To this solution was added n-BuLi (17.6 mL, 44 mmol, 2.5 M in hexane) slowly. The dry ice bath was removed and the reaction mixture was allowed to warm to rt over a period of 1.5 h. This mixture was then cooled to −78° C., and a solution of n-BuLi (20 mmol, 8 mL, 2.5 M in hexane) was added. The reaction mixture was warmed to rt, recooled to −78° C. over a period of 2 h and a neat solution of methyl iodide (5.68 g, 40 mmol) added. The reaction mixture was allowed to warm to rt overnight, quenched with saturated NH4Cl (100 mL) at rt. It was extracted with EtOAc (100 mL). The organic phase was washed with brine (100 mL), dried (MgSO4), and concentrated in vacuo to give a yellow oil which was crystallized from hexane to afford the product as a slightly yellow solid (3.1 g, 81%): 1H NMR (CDCl3) δ 0.79 (m, 2H), 1.36 (s, 9H), 1.52 (m, 2H), 1.62 (s, 3H), 4.10 (bs, 1H).
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])[O:14]1.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Li+].CC([N-]C(C)C)C.Cl>C(OCC)(=O)C.CCOCC>[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH2:20][C:31](=[O:32])[CH2:30][O:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:14]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: O=C(Cl)COCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)OC(=O)C=C(CC(=O)COCc2ccccc2)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
In an argon gas stream, 13.75 ml of n-butyl lithium (1.6M solution in hexane) were added to 60 ml of an ether solution containing 2.35 g (0.022 mol) of diisopropylamine at -20° C. to form LDA. After stirring for 30 minutes, the solution was cooled to -78° C., and 6.93 ml (0.04 mol) of HMPA were added thereto, followed by stirring for 15 minutes. Afterward, a mixture of 2.84 g (0.02 mol) of 2,2-dimethyl-6-methyl-1,3-dioxin-4-one and 60 ml of ether as well as 60 ml of an ether solution containing 1.85 g (0.01 mol) of benzyloxyacetyl chloride were added to LDA. After the temperature was gradually returned to room temperature, 10% hydrochloric acid was added thereto to neutralize the solution, and extraction was then carried out with ether. The resultant organic layer was dried over anhydrous magnesium sulfate. Next, the used solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate =4:1), thereby obtaining 1.95 g (yield 67%) of 2,2-dimethyl-6-(3-benzyloxy-2-oxopropyl)-1,3-dioxin-4-one.