Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)([CH3:29])[C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH2:27])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H]>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[NH:1]([CH3:29])[C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH2:27])=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)cc1)C(N)=O)C(C)C
Yield: 54.5 %

Procedure:
Fmoc-N-Me-Val-N-Me-Tyr(Bzl)—NH2 (802 mg, 1.29 mmol) was dissolved in a mixed solution of MeOH (6 ml) and ethyl acetate (6 ml), mixed with 20% palladium hydroxide-carbon (150 mg), followed by stirring in a hydrogen atmosphere at room temperature for 2 days. The mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol=10:1) to give the titled compound (216 mg, 55%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[C:21]([C:26]#[N:27])=[N:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH:4]1[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8]([O:12][C:20]3[C:21]([C:26]#[N:27])=[N:22][CH:23]=[CH:24][N:25]=3)[CH:9]=[C:10]([CH3:11])[C:5]1=2)[CH3:18]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1nccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nccnc3C#N)cc(C)c21
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.0 g, 4.0 mmol) and 3-chloro-pyrazine-2-carbonitrile (0.84 g, 6.0 mmol) in DMF (24 mL) was added cesium carbonate (2.68 g, 8.8 mmol). The mixture was heated to 80° C. for 2 hrs. The reaction was cooled down, diluted with H2O, acidified to pH 3 with aqueous HCl (1N). The mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (silica, Hexanes/Ethyl acetate=1:4) affording the title compound (1.30 g, 92%) as a white solid. 1H NMR (CDCl3) δ 8.40 (d, 1H), 8.29 (d, 1H), 7.36 (d, 1H), 7.11 (d, 1H), 5.69 (dd, 1H), 4.81 (s, 1H), 4.20 (q, 2H), 3.11 (dd, 1H), 2.44 (dd, 1H), 2.39 (s, 3H), 1.26 (t, 3H). MS found: (M+H)+=354.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[Cl:38][C:39]1[CH:44]=[C:43]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]3)=[N:22][CH:23]=2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 42 %

Procedure:
Following general procedure II, (R)-tert-butyl (1-(5-((6-chloro-3-isobutyryl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (225 mg, 0.63 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (175 mg, 0.66 mmol) to afford the desired product (168 mg, 62%) as a solid: ESI MS m/z 635 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH:17]=3)=[C:11]([F:29])[CH:10]=2)[CH2:4]1.O[C:31]1[CH:35]=[CH:34][O:33][N:32]=1>>[O:33]1[CH:34]=[CH:35][C:31]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]4[CH2:21][CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH:17]=4)=[C:11]([F:29])[CH:10]=3)[CH2:4]2)=[N:32]1
Reactant: O=C1O[C@@H](CO)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Reactant: Oc1ccon1
Product: O=C1O[C@@H](COc2ccon2)CN1c1cc(F)c(C2=CCN(Cc3ccccc3)CC2)c(F)c1

Procedure:
PCT Application No. GB99/01753 (Publication No. WO 99/64417) describes the preparation of 5(R)-Hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one (Reference Example 4 of GB99/01753), which is reacted under Mitsunobu conditions with 3-hydroxyisoxazole to give 5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one (Reference Example 5 of GB99/01753). Purification (by column chromatography) and subsequent reaction with 1-chloroethyl chloroformate and work-up gives 5(R)-Isoxazol-3-yloxymethyl-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one (Reference Example 6 of GB99/01753).
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl-].[Cl-].[Cl-].[Al+3].Cl.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:6])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)CCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
Glutaryl chloride (28.2 g; 0.167 mole) was slowly added to a mixture of anhydrous aluminum trichloride (50 g; 0.375 mole) and 250 ml benzene. The mixture was stirred vigorously in an ice/water bath. After completion of the addition, the ice/water bath was removed and stirring was continued for two hours. The solution obtained was slowly poured into a mixture of 200 g crushed ice and 40 ml concentrated aqueous hydrochloric acid. The resulting product was recovered by extraction and crystallization to produce 1,5-diphenyl-1,5-pentanedione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.[CH3:33][N:34]([CH3:43])[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:40]3[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][N:34]([CH3:43])[CH3:33])[CH2:38][CH2:39]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CN(C)CCN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-pyrimidine-3-amido]-1H-pyrazol-1-yl]acetic acid (100 mg, 0.22 mmol) in DMF (10 mL) was added dimethyl[2-(piperazin-1-yl)ethyl]amine (68 mg, 0.43 mmol), DIEA (125 mg, 0.97 mmol) and HATU (123 mg, 0.32 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Analyse HPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBD Column, 19&#65533; 100 mm 5 um 13 nm; mobile phase, Water with 10 mM NH4CO3 and ACN (15% ACN up to 40% in 6 min); Detector, UV 254/220 nm. This resulted in 79.1 mg (61%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 25) [M+H]+=602.2, RT=0.89 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.7, 7.1 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.48-3.42 (m, 4H), 2.45-2.32 (m, 8H), 2.13 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].[CH3:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([CH3:31])[N:25]=[CH:24][N:23]=1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][CH:9]2[CH2:8][CH2:7][N:6]([C@H:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:28]([C:27]3[C:22]([CH3:21])=[N:23][CH:24]=[N:25][C:26]=3[CH3:31])=[O:29])[CH2:11][CH2:10]2)=[CH:14][CH:15]=1
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: COc1ccc(NC2CCN([C@H](C)CCN)CC2)cc1
Product: COc1ccc(NC2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Yield: 91.8 %

Procedure:
Using general procedure E, [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-amine (see EXAMPLE 230) (1.59 g, 5.48 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (834 mg, 5.48 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide as a white solid (2.07 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.S(Cl)([Cl:16])(=O)=O>>[Cl:1][C:2]1[C:10]([Cl:16])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Product: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Yield: 70 %

Procedure:
Chlorination of 4-chloroisatin with sulfuryl chloride by the method of B. R. Baker, et al., J. Org. Chem., 17, 149 (1952), gave a 70% yield of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19](Cl)[N:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=1>>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=3)[N:18]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCN)ccc1O
Reactant: O=C(Nc1ccc(-c2ccnc(Cl)n2)cc1)OCc1ccccc1
Product: COc1cc(CCNc2nccc(-c3ccc(NC(=O)OCc4ccccc4)cc3)n2)ccc1O

Procedure:
Intermediate 48 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 471. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.28 (m, 1H) 8.0 (d, 2H) 7.5 (d, 2H) 7.4 (m, 4H) 7.05 (s, 1H) 6.9 (d, 1H) 6.83 (m, 1H) 6.7 (m, 2H) 5.55 (br s, 1H) 5.21 (s, 2H) 3.81 (s, 3H) 3.7 (t, 2H) 2.9 (t, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:9].C[O:11][C:12](C)(C)[CH3:13]>C(O)C>[ClH:9].[NH2:2][C:1]([O:11][CH2:12][CH3:13])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC#N
Reactant: COC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C=C(N)OCC
Reaction time: 8 h

Procedure:
A solution of 226 g of ethyl cyanoacetate in 200 ml of absolute ethanol is saturated by introducing hydrochloric acid gas at 0°. The mixture is stirred at 0° overnight and then 1.5 l of tert.butyl methyl ether are added thereto. The ethyl β-amino-β-ethoxyacrylate hydrochloride which thereby precipitates is filtered off under suction, washed portionwise with 0.5 l of tert.butyl methyl ether and dried at 35° in vacuo. There is obtained ethyl β-amino-β-ethoxyacrylate hydrochloride, melting point 103°-104°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: Cc1ccc(B(O)O)cc1
Product: COC(=O)c1c(O)c2ccc(-c3ccc(C)cc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-p-tolyl-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 4-methyl-phenylboronic acid under conditions analogous to Example 7(a). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.23 (s, 1H), 8.38 (d, J=8.7 Hz, 1H), 7.64-7.51 (m, 4H), 7.38-7.26 (m, 2H), 4.02 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)[C:7]([CH3:23])=[CH:6]2.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)[C:7]([CH3:23])=[CH:6]2
Reactant: COC(=O)c1ccc(-c2nc3ccc(OC)cc3cc2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc2cc(O)ccc2nc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.1 %

Procedure:
Methyl 4-(6-methoxy-3-methylquinolin-2-yl)benzoate (37 mg, 0.121 mmol) was dissolved in 2 mL of DCM and BBr3 (150 μL) was added. The mixture was stirred at room temperature for 1 day followed by addition of 10 mL of H2O. The solution was stirred vigorously for 1 h followed by filtration of the solids. The solids were washed with H2O and dried in vacuo to yield 9.5 mg (28% yield) of Compound IV-1. 1H NMR (DMSO-d6, 400 MHz): δ 8.37 (s, 1H), 8.10 (d, 2H), 7.94 (d, 1H), 7.78 (d, 2H), 7.42-7.39 (dd, 1H), 7.24-7.23 (d, 1H), 2.43 (s, 3H). MS (ESI): m/z 280.10 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:23]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:11]2[N:12]=[C:13]([CH3:22])[N:14]=[C:15]([O:16][CH2:17][C:18]([F:21])([F:20])[CH3:19])[C:10]2=[N:9]1.[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:31]#[N:32])[N:9]=[C:10]3[C:15]([O:16][CH2:17][C:18]([F:20])([F:21])[CH3:19])=[N:14][C:13]([CH3:22])=[N:12][C:11]=23)=[CH:25][CH:26]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(OCC(C)(F)F)c2nn(-c3ccccc3Br)c(-c3ccc(Cl)cc3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(OCC(C)(F)F)c2nn(-c3ccccc3C#N)c(-c3ccc(Cl)cc3)c2n1
Temperature: 200 °C

Procedure:
A mixture of 2-(2-bromophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine (10A-7, 50 mg, 0.1 mmol), Zn(CN)2(20 mg, 0.17 mmol), Pd(PPh3)4 (15 mg, 0.01 mmol) in DMF (1 ml) was heated in a microwave apparatus (Emrys Optimizer, Personal Chemistry) at 200° C. for 3 minutes. The reaction mixture was quenched with saturated aqueous NaCl and extracted with ethyl acetate (2×). The combined organic extracts were dried and concentrated under vacuum. The crude residue was purified via HPLC (Shimadzu) using a solvent gradient of 30% CH3CN/hexanes to 100% CH3CN to give the desired product, 2-[3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methylpyrazolo[4,3-d]pyrimidin-2-yl]-benzonitrile (11A-1), as a colorless solid (25 mg): MS (M+1)+440.0; 1H NMR (400 MHz, CDCl3) δ 7.80-7.64 (m, 4H), 7.40-7.26 (m, 4H), 4.8 (t, J=11.6 Hz, 2H), 2.7 (s, 3H), 1.79 (t, J=18.67 Hz, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C@@H:15]2[O:20][C:19]3[C:21]([NH2:26])=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:27](C1NC=CN=1)(C1NC=CN=1)=[O:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[O:20][C:19]3[C:21]4[NH:26][C:27](=[O:28])[NH:25][C:22]=4[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Reaction time: 15 h

Procedure:
To a solution of 0.30 g (0.71 mmole) of [(2R)-7,8-diamino-2,3-dihydro-1,4 benzodioxin-2-yl]methyl 4-methylbenzenesulfonate dihydrochloride in 50 mL of methylene chloride was added 0.50 g (3.0 mmole) of carbonyl diimidazole and 0.65 g (5.0 mmole) of diisopropylethylamine. The reaction mixture was stirred under nitrogen for 15 hours. The mixture was then concentrated in vacuum and 250 mL of ethyl acetate added. This solution was washed with 250 mL portions each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on 25 g of silica gel, using a gradient elution commencing with chloroform and ending with 3% methanol in chloroform. The product fractions were combined and evaporated in vacuum to give 0.21 g of the (R)-enantiomer of the title compound as an off-white solid, m.p. 202-204° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([O:9][CH2:8][C@H:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:21])[CH2:29][CH2:28]2)=[CH:35][CH:34]=1
Reactant: CN1CCO[C@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@H](COC(=O)N2CCN(c3ccc(F)cc3)CC2)C1
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
(S)-(4-Methyl-morpholin-2-yl)-methanol (Intermediate 10; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 314 mg, 0.91 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) and the solvents were removed in vacuo to give [(2S)-4-methylmorpholin-2-yl]methyl 4-(4-fluorophenyl)-piperazine-1-carboxylate (130 mg, 51%) as a light brown solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=1
Reactant: Clc1cnccn1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1ccc(Oc2cnccn2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of chloropyrazine (124 mg, 1.08 mmol), K2CO3 (749 mg, 5.42 mmol), and 4-iodophenol (263 mg, 1.20 mmol) in DMF (24 mL) was heated at 100° C. for 9.5 h and then stirred at rt overnight. The reaction was diluted with EtOAc and washed with H2O (40 mL). The aqueous wash was back extracted with EtOAc (20 mL). The organic extracts were combined, washed with H2O (2×40 mL), washed with brine (40 mL), dried (MgSO4), filtered, concentrated and purified by silica gel chromatography (0%-20% EtOAc in hexanes) to give 289 mg of 2-(4-iodophenoxy)pyrazine (containing 15% of 4-iodophenol) as a white semi-solid. 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, 1H), 8.41 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 2H), 7.07 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[ClH:25]>O1CCOCC1>[ClH:25].[NH:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl 4-[3-(ethoxycarbonyl)phenyl]piperidine-1-carboxylate (3.24 g, 9.72 mmol) was dissolved in anhydrous 4N HCl in dioxane (ca. 30 mL) and stirred at rt for 1.5 h. The reaction mixture was concentrated to give ethyl 3-piperidin-4-ylbenzoate hydrochloride as a pale yellow solid that required no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][OH:18])=[CH:4][CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1[CH2:28][CH2:29][C:30](OCC)=[O:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[C:9]2[CH2:17][O:18][C:24]2[CH:23]=[CH:22][C:21]([CH2:28][CH2:29][CH2:30][OH:31])=[C:20]([F:19])[C:25]=2[F:26])=[CH:6][CH:7]=1
Reactant: OCc1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1F
Product: OCCCc1ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared by reacting the product prepared in Step D of Example 1 and ethyl 3-(2,3-difluoro-4-hydroxyphenyl)propanoate according to the procedure described in Example 1, Step E, and then according to Example 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH:10]([OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:10](=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2O)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
(±)-3-Hydroxy-4-(3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.27 g, 4.13 mmol) and pyridine (334 uL, 4 mmol) in methylene chloride (70 mL) at 0° C. were treated with Dess-Martin periodinane (3.5 g, 8.3 mmol) and then the reaction was stirred at room temperature for 2 h. The reaction was quenched by addition of a mixture of sat. solution of Na2S2O3 and sat. solution of NaHCO3 (1:1 v:v) (50 ml), which was followed by extraction with ether. The product was isolated by flash chromatography to afford (±)-4-(3-methoxy-phenyl)-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.94 g, 75% yield). 1H NMR (CDCl3): δ ppm 7.27 (s, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.70-6.75 (m, 1H), 6.68 (s, 1H), 4.24 (d, J=18.2 Hz, 1H), 4.06 (d, J=18.2 Hz, 2H), 3.80 (s, 3H), 3.62 (dd, J=11.5, 5.9 Hz, 1H), 3.51 (br. s., 1H), 2.19-2.35 (m, 2H), 1.44-1.53 (m, 9H).