Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][C@H:12]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13](OCC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[CH2:1]([O:8][CH2:9][C@H:10]([CH:26]([CH3:28])[CH3:27])[CH2:11][C@H:12]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](C[C@H](COCc1ccccc1)C(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)[C@@H](COCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
To a solution of (2S,4S)-ethyl 4-(benzyloxymethyl)-2-(tert-butoxycarbonylamino)-5-methylhexanoate (16 g, 42.2 mmol) in EtOH (200 mL) at rt was added NaBH4 (12.8 g, 0.338 mol) in portions. The mixture was stirred for 16 h. The solvent was evaporated and the residue was partitioned between H2O (300 mL) and EtOAc (3×200 mL). The combined organic extracts were washed with brine, dried over MgSO4 and evaporated to give tert-butyl (2S,4S)-4-(benzyloxymethyl)-1-hydroxy-5-methylhexan-2-ylcarbamate (14.4 g, 97%). 1H NMR (400 MHz, CDCl3): δ7.35-7.29 (m, 5H), 4.95 (brs, 1H), 4.50 (s, 2H), 3.62 (brs, 3H), 3.50 (m, 1H), 3.35 (m, 1H), 1.75 (m, 1H), 1.54-1.45 (m, 3H), 1.43 (s, 9H), 0.88 (m, 6H); MS: 352 (M++1)
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1.C(Cl)(Cl)Cl>CO>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][C@H:22]([C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1)[CH2:23][OH:24])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](CO)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](CO)c1ccccc1
Yield: 23 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with D-phenylglycinol to provide the title compound in 23% yield as yellow needles (flash chromatography on SiO2, eluent CHCl3, MeOH, AcOH—15, 1, 0.2).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[S:5](=[O:14])[CH2:4][CH2:3]1.C1C[O:19]CC1.OO>C(O)C.ClCCl.[NH4+].[Cl-].[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[S:5](=[O:19])(=[O:14])[CH2:4][CH2:3]1
Reactant: CC1(C)CCS(=O)c2ccc(C=O)cc21
Reactant: C1CCOC1
Agent: O=[Mo](=O)([O-])[O-]
Agent: OO
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: CC1(C)CCS(=O)(=O)c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A solution of 4,4-dimethyl-3,4-dihydro-2H-thiochromene-6-carbaldehyde 1-oxide (148 mg, 0.67 mmol) in ethanol (5.94 mL): THF (2.40 mL) and hydrogen peroxide (2.33 mL, 26.6 mmol, 35 wt. % in water) was treated with ammonium molybdate (26.1 mg, 0.13 mmol) at room temperature. The mixture was stirred at room temperature for 80 minutes before being diluted with dichloromethane (30.0 mL) and saturated aqueous NH4Cl (5.00 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2×, 30.0 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-5% MeOH/dichloromethane to give the desired product as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[CH3:16][N:17]([CH3:27])[C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[CH3:16][N:17]([CH3:27])[C:18]1[CH:23]=[C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH:13]([OH:15])[CH3:14])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: CN(C)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1
Yield: 34.8 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1 using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.5 g, 1.86 mmol), 3-(dimethylamino)phenylboronic acid (0.46 g, 2.79 mmol), Pd(PPh3)4 (0.11 g, 0.093 mmol) and Cs2CO3 (0.78 g, 2.41 mmol) to afford the title compound (0.2 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][CH:12]([CH2:17][OH:18])[CH2:13][CH2:14][CH2:15][CH3:16])=O)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl>>[CH2:13]([CH:12]1[CH2:17][O:18][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:11]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(CO)NC(=O)Nc1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCC1COC(Nc2cccc(Cl)c2)=N1
Reaction time: 8 h

Procedure:
Compound 978 (50 mg) was treated with POCl3 (1.0 mL). This was stirred overnight. The solvent was removed via reduced pressure distillation. The residue was washed with aqueous sodium bicarbonate and then dissolved in EtOAc. The solvent was dried, filtered and evaporated. The residue was dissolved in acetone (1 mL) and refluxed with water (2 mL) for 1.5 hrs. The solution was extracted with EtOAc, the organic layer evaporated and the residue chromatographed on silica to give the target compound. 1H NMR (300 MHz, CDCl3) δ=7.38 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.05 (br, 1H), 7.00 (d, 7.5 Hz, 1H), 4.47 (m, 1H), 3.95 (m, 2H), 1.8-1.2 (m, 6H), 0.95 (m, 3H). ESIMS=224.9 m/z (M+H)
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[N:17][C:16]=3[CH:15]=2)[CH2:9][CH2:8]1)([CH3:6])[C:3]([NH2:5])=[O:4].Br[C:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[O:45][C:44]=1[F:52].[OH-].[Na+]>O1CCOCC1.C(O)C.S1C=CC=C1C([O-])=O.[Cu+].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>[F:52][C:44]1[O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:43]=1[C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:21]2[S:22][C:14]([CH2:13][N:10]3[CH2:9][CH2:8][N:7]([C:2]([CH3:6])([CH3:1])[C:3]([NH2:5])=[O:4])[CH2:12][CH2:11]3)=[CH:15][C:16]=2[N:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: Fc1oc2ccccc2c1Br
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4c(F)oc5ccccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
To a degassed mixture of 2-methyl-2-(4-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide (150 mg, 0.22 mmol), 3-bromo-2-fluorobenzofuran (0.22 mmol), copper(I) thiophene-2-carboxylate (41 mg, 0.22 mmol) in dioxane (2 mL) was added Pd(PPh3)4 (12 mg, 0.011 mmol). The reaction mixture was reacted in the microwave at 140° C. for 35 min. The reaction mixture was filtered through paper and concentrated. The crude product was purified by flash chromatography (20% MeOH in DCM) to give a yellow paste which was dissolved in dioxane (5 mL) and ethanol (1 mL). A 12 M aqueous solution of NaOH was then added. The resulting mixture was then stirred at 65° C. for 15 hours. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column. The column was washed with MeOH and the desired product was then eluted with 2 M NH3 in MeOH and further purified by RP-HPLC to give 163. LCMS: M+H+=539.2. 1H-NMR (400 MHz, DMSO-d6): δ 8.46 (d, 1H), 7.63 (d, 1H), 7.41 (m, 3H), 7.05 (d, 1H), 6.93 (d, 1H), 3.97 (m, 4H), 3.86 (s, 2H), 3.82 (m, 4H), 2.31-2.62 (m, 8H), 1.08 (s, 6H)
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]([CH3:24])[CH:5]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7].[OH-].[Na+].C[CH2:28][O:29]CC.ClC(OC(Cl)(Cl)Cl)=O>C1(C)C=CC=CC=1>[CH3:3][CH:4]([CH:5]1[CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:7][C:28](=[O:29])[N:14]1[CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[CH3:24]
Reactant: CCOCC
Reactant: CC(C)C(NCCCN1CCCCC1)C(O)c1ccccc1
Agent: Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)C1C(c2ccccc2)OC(=O)N1CCCN1CCCCC1
Yield: 93 %

Procedure:
(1RS,2SR)-3-Methyl-1-phenyl-2-(3-piperidinopropylamino)butane-1-ol dihydrochloride (755 mg, 2.00 mmol) was suspended in a 10% aqueons solution of sodium hydroxide (12 ml), followed by addition of ether (28 ml). The mixture was stirred and, when became clear, ice-cooled. A 20% solution of trichloromethyl chloroformate (hereinafter referred to simply as "TCF") in toluene (4.0 ml) was added dropwise over one hour. After completion of the TCF addition, the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, washed once with brine, dried over sodium sulfate and then evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (silica gel: 7 g, solvent: chloroform/methanol=20/1) to obtain 613 mg of the intended compound as pale yellow crystals (yield: 93%).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.[CH3:15][C:16]([CH3:23])([CH3:22])[C:17](=O)[CH2:18][C:19]#[N:20].Cl>CCO>[C:16]([C:17]1[CH:18]=[C:19]([NH2:20])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]([F:13])([F:14])[F:2])=[CH:10][CH:9]=2)[N:12]=1)([CH3:23])([CH3:22])[CH3:15]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C

Procedure:
A solution of (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (1.83 g, 8.01 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.10 g, 8.81 mmol) in a mixture of conc hydrochloric acid (12 M, 2.0 mL) and EtOH (20 mL) was heated at reflux for 18 hr. The mixture was cooled to RT and was partitioned between aq. NaOH (2.0 M, 50 mL) and ether (100 mL). The organic layer was separated and was washed with brine (100 mL) and then dried and evaporated in vacuo to afford the title compound, Intermediate A27, as a yellow solid (2.22 g, 91%); Rt 2.29 min (Method 2); m/z 300 (M+H)+, (ES+).
Reaction SMILES: C12CC(CC1)CC2[O:8][C:9]([C:11]1[C:12]([C:25]([F:28])([F:27])[F:26])=[N:13][C:14]([O:17][C@@H:18]2[CH2:23][C@@H:22]3[CH2:24][C@H:19]2[CH2:20][CH2:21]3)=[N:15][CH:16]=1)=[O:10].C12CC(CC1)CC2OC(C1C(C(F)(F)F)=NC(O[C@H]2C[C@H]3C[C@@H]2CC3)=NC=1)=O.[OH-].[Na+].Cl>C(O)C>[C@H:19]12[CH2:24][C@H:22]([CH2:21][CH2:20]1)[CH2:23][C@H:18]2[O:17][C:14]1[N:13]=[C:12]([C:25]([F:26])([F:27])[F:28])[C:11]([C:9]([OH:10])=[O:8])=[CH:16][N:15]=1
Reactant: O=C(OC1CC2CCC1C2)c1cnc(O[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Agent: Cl
Agent: O=C(OC1CC2CCC1C2)c1cnc(O[C@H]2C[C@@H]3CC[C@H]2C3)nc1C(F)(F)F
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cnc(O[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Reaction time: 1 h
Yield: 130 %

Procedure:
To a solution of a mixture (110 mg) of rac-(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yloxy]-4-(trifluoromethyl)pyrimidine-5-carboxylate and rac-(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl2-[(1S,2S,4R)-bicyclo[2.2.1]hept-2-yloxy]-4-(trifluoromethyl)pyrimidine-5-carboxylate in ethanol (3 mL) was added a 1 M aqueous sodium hydroxide solution (1 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 1 M hydrochloric acid (1 mL), and then the solvent was evaporated under reduced pressure. To the residue was added water, followed by extraction with ethyl acetate. The extracted organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and then the obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol=98:2 to 90:10) to obtain rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yloxy]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (109 mg) as a colorless solid.
Reaction SMILES: COC[C@@H]1[C@H](/C=C/C(/C)=C/C(O)=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1.[CH2:30]([O:32][CH2:33][C@H:34]1[C@@H:36](/[CH:37]=[CH:38]/[C:39](/[CH3:46])=[CH:40]/[C:41]([O:43]CC)=[O:42])[C@:35]1([CH3:61])[C:47]1[CH:56]=[CH:55][C:54]2[C:53]([CH3:58])([CH3:57])[CH2:52][CH2:51][C:50]([CH3:60])([CH3:59])[C:49]=2[CH:48]=1)[CH3:31]>>[CH2:30]([O:32][CH2:33][C@H:34]1[C@@H:36](/[CH:37]=[CH:38]/[C:39](/[CH3:46])=[CH:40]/[C:41]([OH:43])=[O:42])[C@:35]1([CH3:61])[C:47]1[CH:56]=[CH:55][C:54]2[C:53]([CH3:58])([CH3:57])[CH2:52][CH2:51][C:50]([CH3:60])([CH3:59])[C:49]=2[CH:48]=1)[CH3:31]
Reactant: CCOC[C@H]1[C@@H](/C=C/C(C)=C/C(=O)OCC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@@H](/C=C/C(C)=C/C(=O)O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 86 %

Procedure:
Following a procedure similar to that for the preparation of Compound 20a but using Compound 17b as the starting, material afforded the title compound (35 mg, 86% yield) as a white solid:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([NH:22][CH2:23][CH3:24])[N:20]=[CH:21][C:10]=3[C:9]2=[O:25])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)CCC.[F-].[NH4+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([NH:22][C:19]1[N:20]=[CH:21][C:10]2[C:9](=[O:25])[N:8]([C:6]3[CH:7]=[C:2]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[CH:3]=[N:4][CH:5]=3)[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]=2[N:18]=1)[CH3:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(Br)c1)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(-c3ccco3)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Compound 21 (68.0 mg, 0.169 mmol) obtained in Example 21 was dissolved in toluene (4 mL), and the mixture was stirred overnight under reflux after adding tri-n-butyl(2-furyl)tin (106 mg, 0.338 mmol) and bis(triphenylphosphine)palladium dichloride (12.0 mg, 0.0169 mmol). The mixture was cooled to room temperature, vigorously stirred after adding a saturated aqueous ammonium fluoride solution, and filtered through sellite. The filtrate was collected and diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by preparative TLC to give the title compound (Compound 36) (40.9 mg, 62%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].CS(O[CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:15]1[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1)#[N:2]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cccc(C#N)c2)C1
Temperature: 80 °C
Yield: 48.1 %

Procedure:
3-cyanophenol (284 mg, 2.38 mmol, 1.2 eq) is added to a mixture of tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (500 mg, 1.99 mmol, 1 eq) and Cs2CO3 (2.27 g, 6.96 mmol, 3.5 eq) in DMF (20 ml). The reaction is heated overnight at 80° C., then cooled to room temperature. Brine (100 ml) is added and the mixture is extracted twice with diethyl ether. The combined organic phases are washed with brine, dried over MgSO4 and evaporated under reduced pressure. The residue is purified by basic reverse phase chromatography (gradient: acetonitrile/H2O/NH4OH from 50/50/0.1 to 80/20/0.1) to afford 262.4 mg of tert-butyl 3-(3-cyanophenoxy)azetidine-1-carboxylate a1-43.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][N:10]=1.CC(C)([O-])C.[Na+]>CC1C=CC(C)=CC=1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:14]2[C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Nc1cccc2cnccc12
Reactant: Clc1cc(Cl)ncn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccc(C)cc1
Product: Clc1cc(Nc2cccc3cnccc23)ncn1
Temperature: 100 °C
Yield: 17.2 %

Procedure:
A mixture of 4,6-dichloropyrimidine (5 g, 34 mmol), isoquinolin-5-amine (5.3 g, 37 mmol), 2′-(dimethylamino)-2-biphenylyl palladium (II) chloride dinorbornylphosphine complex. [see Angew. Chem., 2002, 41, 3668; CAS number 359803-53-5] (940 mg, 2 mmol) and sodium tert-butoxide (4.8 g, 50 mmol) in p-xylene (100 ml) was degassed thoroughly and heated under nitrogen at 100° C. for 16 hours. The cooled reaction mixture was purified by column chromatography over silica (eluant 1% MeOH in DCM) to give the title compound (1.5 g, 17%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([C:18]([O:20]CC)=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([C:18]([OH:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccccc1-c1ccc(C(=O)OC)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1C(=O)O
Temperature: 100 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of 2-ethyl 4′-methyl 2′-methyl-biphenyl-2,4′-dicarboxylate (2.404 g), ethanol (12 ml) and 4N aqueous sodium hydroxide solution (6 ml) was stirred at 100° C. overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and water (50 ml) was added to the obtained residue. This mixture was adjusted to pH 1 with 6N hydrochloric acid (5 ml), ethanol (10 ml) was added, and the mixture was stirred at room temperature for 10 min. This suspension was filtered, the obtained solid was washed with 20 v/v % ethanol-water (10 ml), air-dried, and dried under reduced pressure at 80° C. to give the title compound (1.957 g, 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.N#N.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[NH2:39].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[F:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:3]=[C:2]([NH:39][C:34]2[N:35]=[CH:36][CH:37]=[CH:38][N:33]=2)[CH:7]=1
Reactant: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(Br)cc(-c3ccc(F)cc3F)c2)cn1
Reactant: Nc1ncccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#N
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(Nc3ncccn3)cc(-c3ccc(F)cc3F)c2)cn1
Temperature: 110 °C
Yield: 11.6 %

Procedure:
A solution of 1-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole (0.075 g, 0.161 mmol) in 1,4-dioxane (3 ml) was degassed by N2 bubbling for 5 min. Pyrimidin-2-amine (0.018 g, 0.193 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Pd2(dba)3 (0.014 g, 0.016 mmol, 0.1 eq.) and xantphos (0.037 g, 0.064 mmol, 0.4 eq.) and Cs2CO3 (0.209 g, 0.644 mmol, 4.0 eq) were added sequentially and the mixture was further degassed for 5 min. and then heated at 110° C. for 16 h. The mixture was filtered on celite bed, quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 2% methanol in ethyl acetate) to yield the title product in 11.6% yield (0.09 g). 1H NMR (400 MHz, DMSO-d6): δ 10.15 (s, 1H), 8.83 (S, 1H), 8.57-8.56 (D, 2H), 8.35 (s, 1H), 8.24 (s, 1H), 8.01-7.97 (s, 3H), 7.84-7.81 (d, 1H), 7.70-7.68 (m, 2H), 7.46-7.432 (m, 2H), 7.280-7.286 (m, 1H), 6.95-6.32 (t, 1H), 3.88 (s, 1H), LC-MS (ESI): Calculated mass: 479.48; Observed mass: 480.1 [M+H]+ (rt: 1.52 min).
Reaction SMILES: N1C=CC=N1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:11](=[O:13])[CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: COC(=O)c1cc(C)cc(OC)c1
Reactant: CSc1nccc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: c1cn[nH]c1
Solvent: C1CCOC1
Product: COc1cc(C)cc(C(=O)Cc2ccnc(SC)n2)c1

Procedure:
For the synthesis of the pyrazole derivative, first, as illustrated in Reaction Scheme 7, methyl 3-methoxy-5-methylbenzoate of Formula 2a is allowed to undergo a nucleophilic attack at its carboxylic carbon by the activated methylene group of 4-methyl-2-(methylthio)-pyrimidine, represented by Formula 10, at room temperature (e.g., 20° C.-30° C.) in the presence of lithium hexamethyldisilazide (LHMDS) in tetrahydrofuran to afford 1-(3-methoxy-5-methylphenyl)-2-(2-methylsulfanylpyrimidin-4-yl)ethanone. The compound of Formula 11 is converted into a pyrazole derivative through a two step successive process. In this regard, the compound of Formula 11 is heated with N,N-dimethylformamide dimethylacetal, successively followed by cyclization with hydrazine hydrate into 3-(3-methoxy-5-methylphenyl)-4-(2-methylthiopyrimidine-4-yl]-1H-pyrazol, represented by Formula 12. Thereafter, the compound of Formula 12 is converted into a cyano compound of Formula 13 by heating with iodoacetonitrile in DMF, subsequently by the oxidation of the sulfide with meta-chloroperbenzoic acid to a sulfone, [4-(2-methanesulfonylpyrimidin-4-yl)-3-(3-methoxy-5-methylphenyl)pyrazol-1-yl]acetonitrile, represented by Formula 14. The sulfone compound of Formula 14 is then subjected to nucleophilic substitution with 3-hydroxyazetidine hydrochloride, and then to demethylation with boron tribromide into [4-[2-(3-hydroxyazetindin-1-yl)-pyrimidin-4-yl]-3-(3-hydroxy-4-methylphenyl)-pyrazol-1-yl]acetonitrile, represented by Formula 16.