Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[Cu](C#N)[C:16]#[N:17]>CN(C)C=O>[C:16]([C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: N#C[Cu]C#N
Reactant: COC(=O)c1cc(F)c(F)c(Br)c1F
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(F)c(C#N)c1F
Yield: 66.2 %

Procedure:
269 g of methyl 3-bromo-2,4,5-trifluoro-benzoate and 108 g of copper cyanide are heated to reflux for 5 hours in 400 ml of dimethylformamide. All volatile constituents of the reaction mixture are then removed by distillation in vacuo. The distillate is then fractionated on a column. 133 g of methyl 3-cyano-2,4,5-trifluoro-benzoate of boiling point 88-89° C./0.01 mbar are obtained.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]([CH:13]([CH2:17][CH3:18])[C:14](=O)[CH3:15])[CH3:12]>>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:11]([CH3:12])[C:13]2([CH2:17][CH3:18])[CH2:14][CH3:15]
Reactant: NNc1ccc(Br)cc1
Reactant: CCC(CC)C(C)=O
Agent: Cl
Product: CCC1(CC)c2cc(Br)ccc2NC1C
Yield: 63.8 %

Procedure:
This compound was prepared according to the procedure for Example 1 using 4-bromo-phenyl hydrazine hydrochloride (5.9 g, 26.3 mmol) and 3-ethyl-2-pentanone (3.0 g, 26.3 mmol). The subtitled compound (4.5 g) was obtained in 65% yield as a yellowish oil: 1H-NMR (CDCl3) δ0.81 (t, J=7.4 Hz, 3H), 0.83 (t, J=7.4 Hz, 3H), 1.18 (d, J=6.5 Hz, 3H), 1.42 (dq, J=14.0, 7.4 Hz, 1H), 1.66 (dq, J=14.0, 7.4 Hz, 3H), 3.73 (q, J=6.5 Hz, 1H), 6.47 (d, J=8.2 Hz, 1H), 7.02 (d, J=2 Hz, 1H), 7.09 (dd, J=8.2, 2.0Hz, 1H); 13C-NMR (CDCl3) δ10.46, 10.66, 17.70 (q), 26.5, 29.67 (t), 52.25 (s), 64.80 (d), 111.64 (s), 112.41, 129.07, 131.58 (d), 139.57, 151.04 (s); MS (EI) m/z 268, 270 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2([CH3:14])[CH2:13][O:12][CH2:11]2)=[C:6]([O:15][CH3:16])[C:5]([O:17][CH:18]([F:20])[F:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[C:40](=[O:44])[NH:39][CH2:38]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][CH:18]([F:20])[O:17][C:5]1[CH:4]=[CH:3][C:2]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[C:40](=[O:44])[NH:39][CH2:38]3)=[C:7]([O:8][CH2:9][C:10]2([CH3:14])[CH2:13][O:12][CH2:11]2)[C:6]=1[O:15][CH3:16]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: COc1c(OC(F)F)ccc(Br)c1OCC1(C)COC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)CNC3=O)c1OCC1(C)COC1
Temperature: 85 °C
Yield: 21.8 %

Procedure:
To a stirring solution of 3-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)-3-methyloxetane (200 mg, 0.566 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h. To this cesium carbonate (551 mg, 1.698 mmol), tetrakis(triphenylphosphine) palladium(0) (32 mg, 0.028 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (176 mg, 0.679 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (50 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: COc1ccc2c(Cl)c(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)sc2c1

Procedure:
Following the 6a synthetic method, using B1 (55.33 mg, 0.25 mmol) instead of A1 gave 6b as a white powder; (88.78 mg, 91.1%). [α]D25: +16.5 (c=0.29, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 8.79 (s, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.34-7.23 (m, 6H), 7.07 (dd, J=2.4, 9.0 Hz, 1H), 5.18-5.12 (m, 1H), 3.89 (s, 3H), 3.43-3.28 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 175.50, 160.91, 159.94, 140.08, 135.36, 132.54, 130.83, 129.51, 128.97, 128.76, 127.41, 124.12, 119.87, 116.45, 113.99, 104.31, 55.71, 54.06, 37.36; HRMS (ESI): calcd for: C19H16ClNO4S [M−H]−=388.0416, obsd [M−H]−=388.0402.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:27])[C@@H:4]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[BH4-].[Na+]>O1CCCC1>[Cl:1][CH2:2][C@@H:3]([OH:27])[C@@H:4]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccc2ccccc2c1)C(=O)CCl)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc2ccccc2c1)[C@H](O)CCl)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The foregoing benzyl [3-chloro-1(S)-[(2-naphthyl)methyl]-2-oxopropyl]carbamate was dissolved in 100 ml of 10% aqueous tetrahydrofuran, cooled to 0° C. and treated with 0.456 g of sodium borohydride which was added carefully as the solid. The mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. The mixture was evaporated to give a white solid which was partitioned between dichloromethane and water. The stirred mixture was carefully acidified to pH 1 with concentrated hydrochloric acid. The phases were separated and the aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulphate and evaporated to give 4.325 g of crude product of melting point 155°-160° C. This crude product was extracted with boiling n-hexane. After removal of the solvent by evaporation the residue was recrystallized from ethyl acetate/n-hexane to give 1.046 g of pure benzyl [3-chloro-2(S)-hydroxy-1(S)-[(2-naphthyl)methyl]propyl]carbamate of melting point 173°-174° C.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([O:18]CC)=[O:17])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCOC(=O)C1CCCCN1C(=O)C(=O)C(C)(C)CC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (0.69 g; 2.43 mmol), 1 N LiOH (5 mL), and methanol (20 mL) was stirred at 0° C. for 30 min and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 50 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 0.61 g (98%) of snow-white solid which did not require further purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH2:12][OH:13].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:20]([O:13][CH2:12][C:11]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[C:9]([O:8][CH3:7])[CH:10]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: COc1cc(COCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a stirred suspension of finely powdered cesium carbonate (8.0 g, 24.5 mmol) was added 3-methoxy-4-nitrobenzyl alcohol (1.5 g, 8.18 mmol), followed by benzyl bromide, (2 mL, 16.4 mmol). After stirring at room temperature for 18 h, the suspension diluted with 100 mL diethyl ether, and washed with 3×50 mL water, then 50 mL brine. The organic phase was dried over MgSO4, filtered through a plug of silica, and concentrated. The resulting orange oil was purified by flash chromatography, eluting with 2:1 hexane-EtOAc, to give 1.87 g, (84%) of the benzyl ether. 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J=8.2 Hz, 1H) 7.3-7.4 (m, 5H), 7.26 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.61 (s, 2H), 4.59 (s, 2H), 3.96 (s, 3H).
Reaction SMILES: [N:1]([C@H:4]1[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:21][C:22](=[O:24])[CH3:23])[C@H:14]([CH3:25])[O:13][CH:5]1[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].C([O-])(O)=[O:27].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[N:1]([C@H:4]1[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:21][C:22](=[O:24])[CH3:23])[C@H:14]([CH3:25])[O:13][CH:5]1[S:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:27])=[N+:2]=[N-:3]
Reactant: O=C([O-])O
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(Sc2ccccc2)[C@H]1N=[N+]=[N-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(S(=O)c2ccccc2)[C@H]1N=[N+]=[N-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenyl 2-azido-3,4-di-O-acetyl-2,6-dideoxy-1-thio-L-galactopyranoside (22) (1.02 g, 2.80 mmol) in 50 mL of CH2Cl2 is added NaHCO3 at room temperature. The reaction mixture is cooled to -78° C., and mCPBA (0.878 g, 2.80 mmol, 50-60%) is added. The reaction mixture is stirred at -78° C. for 30 minutes and then allowed to warm to -40° C. over 1 h. The reaction is quenched with dimethyl sulfide (1 mL) at -40° C. and then poured into a solution of saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×30 mL) The organic layers are combined, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (EtOAc/petroleum ether) to afford the title compound 26 as a mixture of diastereomers.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[F:21][CH:22]([F:47])[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[C:27]2[Sn](CCCC)(CCCC)CCCC>CN(C=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.[Cu]I>[F:47][CH:22]([F:21])[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH3:33])[N:28]=[C:27]2[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC(F)F)cc12
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 72.8 %

Procedure:
2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (224 mg, 629 μmol) and 5-(difluoromethoxy)-1-methyl-3-(tributylstannyl)-1H-indazole (398 mg, 818 μmol.30) were dissolved in DMF (3 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (36.3 mg, 31.4 μmol) and CuI (24.0 mg, 126 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (80 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (217 mg, 458 μmol, 72.9%) as a light brown solid. MS (M+H)+=474; 1H NMR (CDCl3) δ: 10.51 (br. s., 1H), 9.29 (s, 1H), 8.61 (s, 1H), 8.30 (s, 1H), 7.38-7.52 (m, 1H), 7.27-7.36 (m, 1H), 6.69 (t, J=74.8 Hz, 1H), 5.76 (s, 2H), 4.20 (s, 3H), 3.56-3.70 (m, 2H), 0.91-1.02 (m, 2H), −0.08-0.06 (m, 9H).
Reaction SMILES: [CH2:1]([C@H:4]([CH:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH:10]=[CH2:11])[C:5]([OH:7])=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O.CCCCCC>CN(C=O)C>[CH2:1]([C@H:4]([C@H:8]([CH2:9][CH:10]=[CH2:11])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCC(C(=O)OC(C)(C)C)[C@@H](CC=C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CC[C@H](C(=O)OC(C)(C)C)[C@@H](CC=C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2R)-2-allyl-3-(tert-butoxycarbonyl)hex-5-enoic acid, Intermediate S8E (1.8 g, 7.08 mmol) (anti:syn 4:1) in DMF (20 mL) at room temperature was added potassium carbonate (1.956 g, 14.16 mmol), followed by (bromomethyl)benzene (1.010 mL, 8.49 mmol). The reaction mixture was stirred at room temperature for 3 h and filtered to remove solid material. The filtrate was diluted with EtOAc and water. The organic layer was separated and washed with water, brine, dried over MgSO4, filtered, and concentrated to give a crude material. This crude material was purified with ISCO 80 g column, 60 mL/min. 0-20% EtOAc/hexane in 25 min to afford (2R,3S)-1-benzyl 4-tert-butyl 2,3-diallylsuccinate, Intermediate S8F (1.5 g, 4.35 mmol, 61.5% yield) as a colorless liquid. 1H NMR (400 MHz, chloroform-d) δ 7.43-7.31 (m, 5H), 5.81-5.62 (m, 2H), 5.17-5.08 (m, 2H), 5.08-4.96 (m, 4H), 2.84-2.63 (m, 2H), 2.45-2.23 (m, 3H), 2.18 (d, J=1.5 Hz, 1H), 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][CH2:17][C:18]#[N:19].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:38](=[O:53])[C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:40]=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[C:18]([CH2:17][N:16]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:1])([F:20])[F:21])[C:38](=[O:53])[C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:42]=[C:41]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:40]=1)#[N:19]
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: N#CCNc1cnccc1-c1ccccc1OC(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(C(=O)N(CC#N)c2cnccc2-c2ccccc2OC(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-(2-(trifluoromethoxy)phenyl)pyridin-3-ylamino)acetonitrile (0.07 g, 239 μmol) in CH2Cl2 (2 mL) were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (137 mg, 477 μmol, example 223, intermediate d) and DIPEA (123 mg, 167 μL, 955 μmol) and the clear, yellow solution was stirred at room temperature for 18 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.085 g; 65%). MS (ESI): m/z=544.08 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:13][CH2:12]1.[F:14][C:15]([F:22])([F:21])[C@H:16]([OH:20])[CH2:17][CH2:18][OH:19].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH:11]1([C:3]2[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=2[O:20][C@@H:16]([C:15]([F:22])([F:21])[F:14])[CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1
Reactant: OCC[C@@H](O)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C2CC2)c(O[C@H](CCO)C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 20 h
Yield: 5.2 %

Procedure:
6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (8 mg, 5.2%) and its regioisomer; MS (EI) 304.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][CH:20]([NH:23][CH3:24])[CH2:21][CH3:22]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][CH2:9][CH2:10][C:20]([NH:23][CH3:24])([NH:19][CH3:18])[CH2:21][CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(NC)NC
Reactant: ClCCOC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCC(CCOC(c1ccccc1)c1ccccc1)(NC)NC
Yield: 63 %

Procedure:
A mixture of 3 g (12.2 mmole) of 2- (diphenyl-methoxy)ethyl chloride, 5 g (49 mmole) of N,N' -dimethyl-propanediamine and 40 ml of toluene was heated under reflux overnight. At the end of this time, the toluene layer was separated and washed with water; 25 ml of a 10% w/v aqueous solution of acetic acid was then added thereto. The aqueous layer was separated, and a 10% w/v aqueous solution of sodium hydroxide was added to make it alkaline. The mixture was then extracted with diethyl ether, and the solvent was removed by distillation under reuced pressure, to obtain 2.4 g (yield 63%) of the title compound as an oil.
Reaction SMILES: [NH2:1][CH:2]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=1.C(N(CC)CC)C>C1COCC1>[F:12][C:9]([F:10])([F:11])[CH:8]([OH:13])[CH:2]([NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([F:14])=[CH:16][C:17]=1[C:24]([F:27])([F:25])[F:26])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(N)C(O)C(F)(F)F
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.7 g (8.5 mmol) of ethyl 2-amino-4,4,4-trifluoro-3-hydroxybutyrate were dissolved in THF, and initially 1.8 g of 4-fluoro-2-trifluoromethylbenzoic acid and 2.6 g (25.4 mmol) of triethylamine and then, at 5° C., 1.9 g (8.5 mmol) of bis(2-oxo-3-oxazolinidylphosphoryl chloride were added. The mixture was stirred at RT for 16 h. The reaction solution was then concentrated, and the residue was diluted with water and extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed. This gave 3.1 g (93% of theory) of the title compound as a colorless residue.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12](B(O)O)=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:24]([O:26][CH3:27])=[O:25].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.COCCOC.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:29]2[C:30]([CH3:31])=[CH:21][CH:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[CH:28]=2)=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1B(O)O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(-c2c(C)cc(OCc3ccccc3)cc2C)c1
Yield: 70.7 %

Procedure:
[4-(Benzyloxy)-2,6-dimethylphenyl]boronic acid (354 mg, 1.38 mmol) and methyl 3-bromo-4-methylbenzoate (229 mg, 1.00 mmol) were dissolved in a mixture of 2 M aqueous sodium carbonate solution (1.38 mL), toluene (10 mL) and 1,2-dimethoxyethane (1 mL), the air was substituted with argon gas, and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (32.8 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18.3 mg, 0.02 mmol) were added. The reaction mixture was heated under reflux for one day. After cooling the reaction mixture, brine was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-hexane/ethyl acetate=9/1) to give the title compound (255 mg, yield 71%) as a colorless oil.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1.[O-:34][CH2:35][CH3:36].[Na+]>C(O)C>[CH2:35]([O:34][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1)[CH3:36]
Reactant: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(NC(=O)[C@H]2CCCN2c2nc3c(c(Nc4cc(C(C)C)[nH]n4)n2)CCC3)cn1
Temperature: 100 °C
Yield: 1.9 %

Procedure:
A suspension of (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (200 mg, 0.44 mmol) and sodium ethoxide (100 mg, 1.42 mmol) in ethanol (2 mL) was heated at 100° C. in a microwave for 1 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc (50 mL). The solution was washed with saturated sodium bicarbonate solution (20 mL) followed by brine (20 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC followed by chiral HPLC to afford 4 mg of (R)—N-(6-ethoxypyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1HNMR (400 MHz, CDCl3) δ (ppm): 1.18-1.32 (m, 6H), 1.38 (t, 3H), 1.90-2.20 (m, 5H), 2.60-2.77 (m, 3H), 2.84-2.98 (m, 3H), 3.60-3.79 (m, 2H), 4.28 (q, 2H), 4.78 (d, 1H), 6.40 (s, 1H), 6.62 (d, 1H), 6.70 (s, 1H), 7.85 (brs, 1H), 7.79 (s, 1H). The other enantiomer is prepared using the (S) starting material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[N:6][CH:7]=1.[Cu][C:20]#[N:21]>>[C:11]([C:10]1[CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=[CH:16][C:9]=1[O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=1)[C:20]#[N:21])#[N:12]
Reactant: N#C[Cu]
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(Br)c1
Product: N#Cc1cncc(Oc2ccc(CO)cc2C#N)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D5 starting from 2-((5-bromopyridin-3-yl)oxy)-5-(hydroxymethyl)benzonitrile and copper(I) cyanide.