Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]#[CH:43])[CH:37]=1>C1COCC1.CN(C=O)C.O>[C:33]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH3:43])[CH:37]=1)=[CH:24][C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])=[CH:32][CH:31]=2)#[N:34]
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(CC)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
Dissolved 370 mg (4.40 mmol) 2-butynoic acid in 20 ml THF under N2 and chilled to 0° C. Added 484 μl (4.40 mmol) N-methylmorpholine and 572 μl (4.40 mmol) isobutyl chloroformate and stirred for 10 minutes. Added a solution of 500 mg (1.76 mmol) 6-amino-4-[(3-ethynylphenyl)amino]-quinoline-3-carbonitrile in 1 ml DMF and 10 ml THF. Removed ice bath at 15 minutes and stirred overnight at 25° C. Stripped solvent, slurried residue with water, collected solids, and dried in vacuo. Boiled in ethyl acetate, collected solids and dried in vacuo, giving 494 mg of yellow solid: mass spectrum (electrospray m/e): M+H=350.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11](O)[C:10]2=[O:15])[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:29]=[C:30]([Cl:32])[CH:31]=1.O>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]2[CH2:37][CH2:36][N:35]([C@H:11]3[CH2:12][CH2:13][N:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)[C:10]3=[O:15])[CH2:34]2)[CH:29]=[C:30]([Cl:32])[CH:31]=1
Reactant: Clc1cc(Cl)cc(C2CCNC2)c1
Reactant: O=C1[C@H](O)CCN1c1cc(F)cc(F)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)cc(F)c1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
Synthesized according to General Procedure 10. To a solution of (R)-1-(3,5-difluorophenyl)-3-hydroxypyrrolidin-2-one (213 mg, 1.0 mmol) in DCM (0.7 mL) at −20° C. was added DIEA (259 mg, 348 μL, 2.0 mmol) followed by the dropwise addition of triflic anyhydride (282 mg, 168 μL, 1.0 mmol) and the reaction mixture was stirred at −20° C. for 45 min. A solution of 3-(3,5-dichlorophenyl)pyrrolidine (216 mg, 1.0 mmol) in DCM (0.7 mL) was added dropwise and the reaction mixture was stirred at −20° C. for 16 hours. The reaction mixture was poured into water and extracted with EtOAc (3 ×). The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness. Purification by silica gel chromatography (0-20% EtOAC in DCM) afforded (3′S)-3-(3,5-dichlorophenyl)-1′-(3,5-difluorophenyl)-1,3′-bipyrrolidin-2′-one as an oil that solidified upon standing (210 mg, 51%).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([C:23](=O)[CH2:24][C:25]#[N:26])=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[CH3:15])=[O:7]>CCO>[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([C:23]2[NH:2][N:3]=[C:25]([NH2:26])[CH:24]=2)=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[CH3:15])=[O:7]
Reactant: NN
Reactant: COC(=O)c1sc(C(=O)CC#N)cc1OC(C)c1ccccc1Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1sc(-c2cc(N)n[nH]2)cc1OC(C)c1ccccc1Cl
Temperature: 80 °C
Yield: 28.1 %

Procedure:
Hydrazine hydrate (17.4 mg, 0.35 mmol, 1.1 Eq.) was added to a stirred solution of 3-[1-(2-Chlorophenyl)-ethoxy]-5-cyanoacetyl-thiophene-2-carboxylic acid methyl ester (115 mg, 0.32 mmol, 1.0 Eq.) in EtOH (4 mL) and the reaction heated at 80° C. overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (70/9/1 DCM/MeOH/Aq. NH3) to give the sub-title compound as a white solid (35 mg, 0.09 mmol, 29%);
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:34](=[O:35])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: COCCOC(=O)Cl
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: COCCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and 2-methoxyethyl chloroformate by using the same method as in Example 107.
Reaction SMILES: Cl[C:2](Cl)(Cl)C(O)=O.C([Zn]CC)C.ICI.[N+:16]([C:19]1[C:28]([O:29][CH:30]=[CH2:31])=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])([O-:18])=[O:17]>ClCCl>[CH:30]1([O:29][C:28]2[C:19]([N+:16]([O-:18])=[O:17])=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:2][CH2:31]1
Reactant: C=COc1cccc(C(=O)OC)c1[N+](=O)[O-]
Reactant: O=C(O)C(Cl)(Cl)Cl
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Product: COC(=O)c1cccc(OC2CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
In a 3 necked, 500 mL flask, a solution of 2,2,2-trichloroacetic acid (16.30 g, 100 mmol) in dichloromethane (100 mL) was slowly added via an addition funnel to a −10° C. solution of diethylzinc (1M hexanes, 100 mL, 100 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 min. Next, diiodomethane (8 mL, 100 mmol) was dropwise added by syringe, and the reaction solution was stirred for 10 min. A solution of methyl 2-nitro-3-(vinyloxy)benzoate (7.42 g, 33.2 mmol) in dichloromethane (20 mL) was added slowly via an addition funnel. The solution was allowed to warm to room temperature overnight. The reaction mixture was cooled to 0° C. and quenched with 1M HCl. The reaction solution was transferred to a separatory funnel, and the aqueous layer extracted with dichloromethane (3×). The combined extracts were washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product mixture was purified by ISCO (0% of EtOAc/heptane in 15 minutes, 220 g column) to provide methyl 3-cyclopropoxy-2-nitrobenzoate (4.7 g, 19.81 mmol, 60.0% yield). HPLC: RT=2.66 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=260 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.68-7.57 (m, 2H), 7.57-7.41 (m, 1H), 4.03-3.82 (m, 4H), 0.94-0.78 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:13]([O:14][CH3:15])=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[I-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:15][O:14][C:13]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:7][C:8]([N+:16]([O-:18])=[O:17])=[C:9]([CH:12]=1)[CH:10]=[O:11]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCCl
Reactant: C1COCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 19 h
Yield: 53.4 %

Procedure:
4-(3-Chloropropyloxy)-5-methoxy-2-nitrobenzaldehyde (0.40 g, 1.5 mmol) was dissolved in toluene (6.0 mL) and the solution was added with potassium carbonate (1.0 g, 7.3 mmol) dissolved in morpholine (0.38 mL, 4.4 mmol), sodium iodide (0.44 g, 2.9 mmol), tetrabutylammonium bromide (24 mg, 0.007 mmol) and water (2.0 mL), followed by stirring at 100° C. for 19 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 0/100) and concentrated to obtain 5-methoxy-4-[3-(morpholin-4-yl)propyloxy]-2-nitrobenzaldehyde (0.26 g, 54%).
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[C:15]([Cl:23])[CH:14]=1.[Li]CCCC.CN(C=O)C>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:8]=[O:9])=[CH:14][C:15]=1[Cl:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(Br)cc1Cl
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C=O)cc1Cl
Yield: 82 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 4-bromo-1-tert-butyl-2-chloro-benzene (200 mg, 0.81 mmol), nBuLi (0.66 ml, 1.6M solution in hexane, 1.05 mmol) and DMF (251 μl, 3.23 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-tert-butyl-3-chloro-benzaldehyde (130 mg, 82%) as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 9.94 (s, 1H), 7.85 (d, J=2 Hz, 1H), 7.70 (dd, J=2 and 8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[N:10]2[N:11]=[CH:12][C:13](I)=[C:9]2[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1)#[CH:23]>>[C:1]([C:5]1[N:10]2[N:11]=[CH:12][C:13]([C:23]#[C:22][C:24]3[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=3)=[C:9]2[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(S(N)(=O)=O)s1
Product: CC(C)(C)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)s3)cnn12

Procedure:
The title compound was prepared from 7-tert.-butyl-5-(4-chloro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrimidine (70 mg, 0.17 mmol) and 5-ethynyl-thiophene-2-sulfonamide (example D.3) (32 mg, 0.17 mmol) according to general procedure II. Obtained as a yellow solid (28 mg, 28%). MS (ISP) 471.1 [(M+H)+]; mp 253–255° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[O:27][CH:28](C)[CH3:29])[CH2:16][C:15]2[C:17]3[C:11]([CH:12]=[CH:13][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:6]1)=[O:4].[OH-].[K+].O.[CH3:35]CO>>[CH2:28]([O:27][C:21]1[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:5]1([C:3]([OH:2])=[O:4])[CH2:16][C:15]2[C:17]3[C:11]([CH:12]=[CH:13][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:6]1)=[O:31])[CH:29]=[CH2:35]
Reactant: COC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2cccc3cccc(c23)C1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
The mixture of 2-(2-isopropoxy-3-methyl-benzoylamino)-2,3-dihydro-1H-phenalene-2-carboxylic acid methyl ester (25) (143 mg, 0.34 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (26) as white solid (127 mg, 93%).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)#[CH:12].N>>[F:19][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1cccc(F)c1
Agent: N
Product: Fc1cccc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-3-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.51 (m, 1H), 7.67 (td, J=8.1, 5.9 Hz, 1H), 7.73-7.82 (m, 2H), 7.86 (s, 1H), 9.32 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][S:7][CH2:8][CH2:9][O:10][P:11]([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])=[O:12])[NH2:5].C(N(C(C)C)CC)(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:6][S:7][CH2:8][CH2:9][O:10][P:11]([N:13]([CH2:14][CH2:15][Cl:16])[CH2:17][CH2:18][Cl:19])([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])=[O:12])[NH:5][S:38]([CH3:37])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H](N)CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)NS(C)(=O)=O
Reaction time: 8 h

Procedure:
3-[[2-[[Bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-L-alanine methyl ester, 400 mg (0.8 mmol), was dissolved in 4 mL anhydrous tetrahydrofuran, and 550 μL (3.2 mmol) diisopropylethylamine added, followed by methanesulfonyl chloride, 181 mg (1.6 mmol). The reaction mixture was purged with argon and stirred overnight. After adding a further 275 μL (1.6 mmol) diisopropylethylamine, then tris(2-aminoethyl)amine-polystyrene resin, 480 mg (1.6 mmol), the mixture was agitated for 6 hours, then filtered and the filtrate evaporated to dryness under vacuum, giving N-(methanesulfonyl)-3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]-L-alanine methyl ester, 397 mg. Purity was verified with ELSD and identity verified with 1H and 31P NMR.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[O:3].[Na+].[OH-].[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.Cl>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
Sodium pyruvate (24.2 g, 0.22 moL) was added to a cold (0° C.) solution of 1N sodium hydroxide (200 mL) and ethanol (10 mL). p-Chlorobenzaldehyde (28.11 g, 0.20 moL) was then added, maintaining the temperature below 5° C. The reaction mixture was aged six hours at 0°-5° C. and then allowed to warm to 20° C. where it was aged an additional six hours to effect complete reaction. The mixture was cooled to -10° C. and the pH adjusted to 1.0 with cold 6N HCl. The p-chlorobenzalpyruvic acid product was then extracted with 800 mL ethyl acetate in 94% yield.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Br:7][C:8]1[C:9]([Cl:15])=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:5]#[N:6])=[N:10][C:9]=1[Cl:15]
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cccc(Br)c1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Br)c(Cl)n1
Temperature: 50 °C

Procedure:
Trimethylsilyl cyanide (19 mL, 0.15 mol) was added to a stirred solution of 3-bromo-2-chloropyridine 1-oxide (C27) (31.6 g, 0.152 mol) and triethylamine (63.4 mL, 0.46 mol) in acetonitrile (400 mL). The reaction mixture was heated to 50° C. for 2 hours. It was then cooled to room temperature and additional trimethylsilyl cyanide (19 mL, 0.15 mol) was added. After the reaction mixture was heated at 50° C. for 1.5 hours, a final portion of trimethylsilyl cyanide (28.5 mL, 0.23 mol) was added and the reaction was heated at reflux for 3 days. After dilution with dichloromethane (2 L), the reaction was washed with saturated aqueous sodium bicarbonate solution (800 mL), then with water (1 L), dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 20% to 25% ethyl acetate in heptane) afforded the title compound as a yellow solid. Yield: 14.92 g, 68.6 mmol, 45%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][CH2:20][C:21]1[O:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:24]3[N:25]=[C:21]([CH2:20][Cl:19])[O:22][CH:23]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1coc(CCl)n1
Product: C[C@]1(c2cc(NC(=O)c3coc(CCl)n3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2-chloromethyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a colorless viscous oil. MS (ISP): m/z=403.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.[Cl-].[CH3:15][O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:19]([C:18]1[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=1[O:16][CH3:15])[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[C:8]([OH:13])[CH:7]=[CH:6]2
Reactant: COc1ccccc1C=[N+]1CCCCC1
Reactant: COc1ccc2cc(O)ccc2c1
Agent: [Cl-]
Product: COc1ccc2c(C(c3ccccc3OC)N3CCCCC3)c(O)ccc2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 6-methoxy-2-naphthol and 1-(2-methoxy-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 32.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][CH:17]=3)[O:9][N:8]=2)[CH:2]=1.[BH4-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]([OH:20])[CH3:19])[CH:15]=[CH:16][CH:17]=3)[O:9][N:8]=2)[CH:2]=1
Reactant: CC(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
A solution of the product of Example 68 (265 mg, 1.0 mmol) in ethanol (5 mL) was stirred with sodium borohydride (Aldrich, 83 mg, 2.2 mmol) at room temperature for 16 hours. The inorganic solid was filtered off with a syringe filter and the liquid mixture was purified by preparative HPLC (Gilson, column, Xbridge® 5 μm, 30×100 mm. eluting solvent, acetonitrile/water (pH=10, NH4HCO3—NH3.H2O buffer), v. 5/95 to 95/5 over 35 minutes, flow rate, 40 mL/minute, uv, 234 nm). Fractions of the desired product were collected and concentrated to give the desired product. 1H NMR (300 MHz, CD3OD) δ 1.51 (d, J=6.7 Hz, 3H), 4.97 (q, J=6.6 Hz, 1H), 7.57-7.73 (m, 3H), 8.13 (dt, J=7.6, 1.5 Hz, 1H), 8.28 (t, J=1.8 Hz, 1H), 8.57 (dt, J=7.9, 1.8 Hz, 1H), 8.74 (dd, J=5.0, 1.8 Hz, 1H), 9.30 (dd, J=2.2, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 268 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=1)[N:5]=2.[CH3:31][C@H:32]1[CH2:37][NH:36][CH2:35][C@@H:34]([CH3:38])[NH:33]1>CS(C)=O>[CH3:31][C@H:32]1[NH:33][C@@H:34]([CH3:38])[CH2:35][N:36]([C:2]2[N:3]([CH2:25][CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[C:6]([C:17]2[CH:18]=[N:19][C:20]([NH:23][CH3:24])=[N:21][CH:22]=2)[N:5]=3)[CH2:37]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Solvent: CS(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4C[C@@H](C)N[C@@H](C)C4)n(CC4CCOC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]-N-methylpyrimidin-2-amine (100 mg, 0.23 mmol), cis-2,6-dimethylpiperazine (80 mg, 0.70 mmol), and dimethyl sulfoxide (1 ml) was stirred at 150° C. for 2 hours. The mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (64 mg, 54%) as a light brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:27]([CH:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:35]([CH:34]([NH:42][C:9]([C@H:7]1[O:8][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NC(Cc1ccccc1)Cc1ccccc1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)NC(Cc1ccccc1)Cc1ccccc1

Procedure:
The reactions and treatments of Example 1 were repeated using (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid (1.01 g, 6.31 mmol.), N-hydroxysuccimide (726 mg, 6.31 mmol.), N,N'-dicyclohexylcarbodiimide (1.30 g, 6.31 mmol.), and α-benzylphenethylamine (1.43 g, 6.31 mmol.). Thus prepared product was purified by silica gel column chromatography (chloroform/methanol=50/1) to give the desired compound as a pale yellow oil (2.22 g, yield: quantitatively).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([CH2:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: OCc1ccccc1
Reactant: CC(=O)Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Product: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Reaction time: 48 h

Procedure:
4-Acetonylbenzoyl chloride (3.92 g) and benzyl alcohol (2.16 g) were refluxed in benzene for 4 hours and then left at room temperature for 48 hours. Removal of the solvent gave the title compound. τ (CDCl3) 7.9 (3H, s), 6.32 (2H, s), 4.69 (2H, s), 2.78 (2H, d, J=8 Hz), 2.70 (5H, m), 1.99 (2H, d, J=8 Hz).
Reaction SMILES: [C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([Cl:19])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@H]1CCC=C[C@H]1c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)[C@H]1CCC=C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 155 mg (1.02 mmol) of 1(R)-phenyl-2(S)-carboxy cyclohex-5-ene (See U.S. Pat. No. 5,750,549, Example 158, Step B) in 3 mL of CH2Cl2 at 0° C. was added oxalyl chloride (100 uL) followed by DMF (1 drop). The reaction was allowed to warm to room temperature. After stirring 1 hour the reaction was concentrated in vacuo, redissolved in CH2Cl2 and concentrated to a yellow solid which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:13][CH2:14][CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][CH2:16][CH2:15][CH:14]=[CH2:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C=CCCBr
Reactant: O=Cc1cc(Br)cc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCOc1c(F)cc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde from step 4A (2.0 g, 9.13 mmol) in DMF (36.5 ml) was added 4-bromo-1-butene (3.71 ml, 36.5 mmol) and potassium carbonate (1.58 g, 11.4 mmol). The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3×30 mL) and brine (30 mL), dried over magnesium sulfate, and then filtered and concentrated in vacuo. Purification by silica gel column chromatography (0-20% EtOAc/hexanes) gave 5-bromo-2-(but-3-enyloxy)-3-fluorobenzaldehyde (2.38 g, 8.71 mmol, 95% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.22 (d, J=0.9 Hz, 1H), 7.98 (dd, J=11.3, 2.4 Hz, 1H), 7.63 (dd, J=2.4, 1.2 Hz, 1H), 5.89 (ddt, J=17.1, 10.4, 6.7 Hz, 1H), 5.17 (dd, J=17.2, 1.7 Hz, 1H), 5.12-5.07 (m, 1H), 4.29 (t, J=6.4 Hz, 1H), 2.57-2.49 (m, 3H).