Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Br)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:24][N:25]2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:38]3[CH2:37][CH2:36][CH:35]([C:23]4[C:22]5[C:26](=[CH:27][C:19]([F:18])=[CH:20][CH:21]=5)[N:25]([C:28]5[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=5)[N:24]=4)[CH2:40][CH2:39]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2CCBr)C1
Reactant: Fc1ccc(-n2nc(C3CCNCC3)c3ccc(F)cc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(c3nn(-c4ccc(F)cc4)c4cc(F)ccc34)CC2)C1
Reaction time: 8 h
Yield: 60.9 %

Procedure:
A mixture of 334 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 420 mg of 4-(6-fluoro-1-(4-fluorophenyl)-1H-indazol-3-yl)piperidine hydrochloride, 500 mg of potassium carbonate and 216 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 8520 C. for 8 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 360 mg of 6-acetyl-3-(2-(4-(6-fluoro-1-(4-fluorophenyl)-1H-indazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 193°-196° C. as oxalate thereof.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:15][C:16]1[CH:29]=[CH:28][C:27]2[O:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Br:30])[CH:24]=3)[CH:19]([CH2:31]O)[C:18]=2[CH:17]=1>C1(C)C=CC=CC=1>[Br:15][C:16]1[CH:17]=[CH:18][C:27]2[O:26][C:25]3[CH:24]=[C:23]([Br:30])[CH:22]=[CH:21][C:20]=3[CH:19]=[CH:31][C:28]=2[CH:29]=1
Reactant: OCC1c2ccc(Br)cc2Oc2ccc(Br)cc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)C=Cc1ccc(Br)cc1O2
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Phosphorus pentoxide (5.04 g, 35.5 mmol) was added portion-wisely to a stirred solution of (2,6-dibromo-9H-xanthen-9-yl)methanol (10-1) (1.01 g, 2.73 mmol) in toluene (100 mL) and the suspension was heated under reflux for 20 min. The mixture was allowed to cool to rt and toluene was removed by decantation. The residual solid was washed with toluene (2×100 mL) by further decantation. The combined organics were cooled in an ice bath and brine (400 mL) was added slowly. The layers were separated and the organic washed with water (300 mL), brine (300 mL), dried over anhydrous MgSO4 and evaporated to dryness, to give a yellow oily solid. The product was purified by column chromatography (SiO2, O-10% EtOAc/isohexanes) to give 2,7-dibromodibenzo[b,f]oxepine (10-2) (763 mg, 79% yield) as a clear oil. 1H NMR (CDCl3): δ 7.41-7.36 (1H, m), 7.33-7.31 (1H, m), 7.29-7.24 (2H, m), 7.04-6.99 (2H, m), 6.68-6.57 (2H, m) ppm.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[CH2:48]([O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:52])[CH3:49].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.CC(=O)OCC>[CH2:48]([O:50][C:51]([N:53]1[CH2:54][CH2:55][N:56]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:57][CH2:58]1)=[O:52])[CH3:49]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 0.25 h

Procedure:
Z-Gly-OH (2.09 g), HOBT hydrate (1.57 g), DIPEA (1.76 ml) and EDCI hydrochloride (1.96 g) were dissolved in DCM/DMF (60 ml/15 ml). After 15 min stirring, 1-ethoxycarbonylpiperazine (1.49 ml) was added and the stirring was continued overnight at RT. EA and a NaHCO3 solution were added to the mixture and the phases were separated. The org. phase was washed with a 1M NaHSO4 solution and a NaCl solution, dried (Na2SO4) and evaporated off. After HV drying, 3.5 g of the desired product were obtained.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[CH3:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C:34](O)=[O:35])=[CH:24][N:23]=1>>[CH3:21][C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([C:34]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:35])=[CH:24][N:23]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Product: Cc1ncc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c(-c2ccccc2)n1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-4-phenyl-pyrimidine-5-carboxylic acid. LC-MS (basic): tR=1.27 min; [M+H]+=471.2.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:29][C:30]([NH2:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O.N>ClCCl>[C:33]([N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]3[N:12]=[CH:11][C:10]([CH2:29][C:30]([NH2:32])=[O:31])=[C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCCNCC3)cc2)cc1NCc1ccccc1
Agent: N
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
25 mg of 4-(benzylamino)-6-{[4-(1,4-diazepan-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 226) was dissolved in 1.5 mL of dichloromethane, to which, under ice cooling, 15.1 mg of acetic anhydride was added, and stirred for 30 minutes. To the reaction mixture 1.5 mL of ammonia water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1), recrystallized from chloroform-methanol-diethylether to obtain 20 mg (73%) of the title compound as light brown needle crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:48]([N:43]1[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41][CH2:42]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 48% yield. LCMS for C31H31ClN7O2 (M+H)+: m/z=568.2.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24](=[O:26])[CH3:25])=[CH:14][CH:13]=2)(C)(C)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[C:24]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:27])[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:9]([CH2:8][NH2:7])=[C:18]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:26])[CH3:25]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(C)=O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(C(C)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Tert-butyl(6-acetyl-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.13 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diisopropyl ether to give 6-acetyl-3-(aminomethyl)-4-butoxy-2-isobutyl-1(2H)-isoquinolinone hydrochloride (0.10 g, 90.9%) as crystals.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][C:13](OCC)=[O:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1csc(-c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1csc(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
Reduction of the latter ester to the title compound is effected as follows: The ester (159 g) is dissolved in dry tetrahydrofuran (250 ml) and added dropwise during 30 min to a stirred mixture of lithium aluminum hydride (50 g) in tetrahydrofuran. The mixture is stirred for one hour, cooled and water (150 ml) is slowly added. The mixture is dried over magnesium sulfate and evaporated to give the title compound as a yellow oil, γmaxCHCl3 3610, 3420 and 1520 cm- 1.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]3=[O:36])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
1.45 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (5.28 mmol), 1.5 g of N-(4-bromobutyl)phthalimid (5.28 mmol) and 0.8 g of triethylamine (7.9 mmol) were dissolved in 20 ml of dimethylformamide and stirred for 16 h at room temperature. The reaction mixture was extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The oily residue began to crystallise upon standing, was stirred with acetonitrile, and finally filtered to yield 0.55 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:14][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[S:14][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc([N+](=O)[O-])c3)s2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCN(c2ncc(-c3cccc(N)c3)s2)CC1
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 1-[5-(3-nitrophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate (75 mg, 0.21 mmol) in ethyl acetate (1.9 mL) and acetic acid (0.19 mL) was added 10% palladium on carbon (22 mg, 0.021 mmol), and the mixture was stirred under an atmosphere of hydrogen (balloon) for 3 hours. The mixture was filtered through celite, washing with ethyl acetate and the filtrate concentrated under reduced pressure. Purification by CombiFlash (30-70% ethyl acetate:hexanes) provided 60 mg (0.18 mmol, 87% yield) of ethyl 1-[5-(3-aminophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3[C:18]2[N:17]=[N:16][N:15]([C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])=[CH:10][CH:11]=3)[CH:19]=2)[CH2:30][CH2:31]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(C5CCNCC5)cc34)nn2)cc1)N1CCOCC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Temperature: 25 °C

Procedure:
To a solution of 3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-piperidin-4-yl-1H-indazole (100 mg; 0.22 mmol; 1.0 eq.) in Pyridine (1.5 mL) was added acetyl chlorid (15 μl; 0.22 mmol; 1.0 eq.). The reaction mixture was stirred at room temperature O/N. Acetyl chlorid (15 μl; 0.22 mmol; 1.0 eq.) was added again to the reaction mixture to complete the reaction. Pyridine was removed under reduced pressure and DCM was added to the residue. DCM phase was washed with a saturated solution of NH4Cl and brine, dried over magnesium sulfate, flittered and concentrated. The crude was purified by preparative chromatography to give the title compound as a white foam. 1H NMR (300 MHz, DMSO-d6) δ 13.30 (brs, 1H), 9.37 (s, 1H), 8.23-8.07 (m, 3H), 7.74-7.64 (m, 2H), 7.55 (d, J=8.6 Hz, 1H), 7.37 (dd, J=8.7 Hz, 1.4, 1H), 4.66-4.50 (m, 1H), 3.97 (d, J=13.2 Hz, 1H), 3.79-3.34 (m, 8H), 3.25-3.09 (m, 1H), 3.03-2.86 (m, 1H), 2.72-2.55 (m, 1H), 2.06 (s, 3H), 1.96-1.44 (m, 4H). HPLC (Condition A): Rt 3.09 min (purity 94.3%). MS (ESI+): 500.3, MS (ESI−): 498.3.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1>CO.O>[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCOCC1
Temperature: 50 °C
Reaction time: 7 h
Yield: 69.3 %

Procedure:
Add 40% w/w sodium hydroxide in water (264.5 mL, 1.15 eq) to a solution of methyl tetrahydro-2H-pyran-4-carboxylate (500 g, 3.47 mol) in methanol (2.26 L). Stir at 50° C. for seven hours. Evaporate solvent, dissolve residue in water (2 L) and wash with methyl-tert-butyl ether (2×1.2 L). Add aqueous 35% hydrochloric acid to the aqueous layer (adjusting pH to 4) and extract with methyl tert-butyl ether (2×1.2 L). Dry over anhydrous magnesium sulfate and concentrate in vacuo. As material still contains water, dissolve the solid in dichloromethane and discard the aqueous layer. Dry the organics with anhydrous sodium sulfate and concentrate in vacuo to give tetrahydro-2H-pyran-4-carboxylic acid (312.76 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 11.21 (br s, 1H), 3.97 (m, 2H), 3.44 (m, 2H), 2.56 (m, 1H), 1.81 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>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>[Br:27][C:28]1[N:29]=[C:30]([C:8]2[CH:7]=[CH:6][C:5]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:4][C:3]=2[O:2][CH3:1])[CH:31]=[CH:32][CH:33]=1
Reactant: Brc1ccccn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (200 mg, 0.57 mmol) CsF (350 mg, 2.3 mmol), Pd(Ph3P)4 (65 mg, 0.057 mmol), and 2-bromopyridine (140 mg, 0.57 mmol) were combined in a 2-neck flask. The flask was evacuated and filled with argon and DME (5 mL) was added. The suspension was deoxygenated with a stream of argon for 10 min. The reaction mixture was stirred under argon at 80° C. for 24 h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using and EtOAc/hexanes gradient to afford the desired 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.08–8.05 (d, 1H), 7.98–7.95 (m, 2H), 7.89 (s, 1H), 7.84–7.79 (m, 1H), 7.63–7.60 (m, 1H), 7.45–7.38 (m, 3H), 4.02 (s, 3H). MS (ESI) 382 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17](=[S:19])[NH2:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C>CN(C)C=O.O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]1[S:19][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(CN2C(=O)CC[C@@H]2CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C

Procedure:
To a solution of the compound 68 (4.50 g) in dimethylformamide (15.0 mL) was ethyl bromopyruvate (2.33 mL) at 0° C. and the solution was stirred at room temperature for 2 Hours. To the reaction solution were added imidazole (4.08 g) and tert-butyldimethylsilyl chloride (4.52 g) at 0° C. and the solution was stirred at room temperature for 2 Hours. To the reaction solution were added ethyl acetate and water and then the solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with an aqueous saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:2→2:3) to give the title compound (4.75 g) having the following physical data.
Reaction SMILES: [CH2:1]([CH:8]1[C:12](=O)O[NH:10][N:9]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([Sn:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])#C>C1(C)C(C)=CC=CC=1>[CH2:1]([C:8]1[N:9]([CH3:14])[N:10]=[C:15]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1NOC(=O)C1Cc1ccccc1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: CCCC[Sn](CCCC)(CCCC)c1cc(Cc2ccccc2)n(C)n1
Temperature: 140 °C

Procedure:
4-Benzyl-3-methyl-1,2,3-oxadiazol-5-one (0.600 g) and ethynyltri-n-butyltin (2.5 ml) were dissolved in xylene (10 ml) and heated to 140° C. under argon for 16 h. The solvent was then evaporated and the residue was chromatographed over silica gel. Elution with a gradient of 0 to 10% acetone/toluene gave the product as a yellow oil (0.189 g); dH (CDCl3) 0.8-1.7 (27H, m), 3.77 (3H, s), 4.00 (2H, s), 6.09 (1H, s), 7.10-7.40 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].Cl.[OH2:12]>C1COCC1.C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:2]2[CH2:3][CH2:4][C:5](=[O:12])[CH2:6][CH2:7]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O=CO
Product: O=C1CCC(c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Grignard reagent was prepared from 50.0 g (259 mmol) of 3,5-difluorobromobenzene and 6.32 g (260 mmol) of dried magnesium in 350 ml of THF, and cooled down to 0° C. Solution of 40.6 g (260 mmol) of a commercially available cyclohexanedionemonoethylene ketal in 300 ml of THF was added dropwise thereto. After finishing of the dropping, the reaction product was warmed up to room temperature and stirred for 3 hours. The reaction product was added to 500 ml of 6N hydrochloric acid, the product was extracted with toluene, washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and the solvent was distilled off. To the residue was added 100 ml of toluene and 5 g of p-toluene sulfonic acid (hereinafter abbreviated to PTS) and refluxed for 5 hours with the water formed by the reaction being removed by a Dean and Stark. Subsequently, 2 g of ethylene glycol was added and refluxed for 2 hours. To the reaction product was added 200 ml of water, the organic layer was washed with saturated aqueous sodium bicarbonate solution and water in turn, dried over magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography treatment using toluene/ethyl acetate (4/1) as eluent, and then subjected to hydrogenation in ethanol using 2.02 g of 5% Pd/C as catalyst. After termination of the reaction, the catalyst was filtered off, and the ethanol was distilled off. After the concentrated product thus obtained was refluxed in 150 ml of formic acid for 3 hours, 400 ml of water was added to the reaction product, the product was extracted with toluene, the extract was washed with saturated aqueous sodium bicarbonate solution and water in turn, the toluene layer was dried over magnesium sulfate, and then the toluene was distilled off to obtain 20.2 g (96.1 mmol) of 4-(3,5-difluorophenyl)cyclohexanone. Yield of this product from 3,5-difluorobromobenzene was 37.1%.
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:9]=1)([CH3:5])[CH3:4].S(Cl)(Cl)=O>C(OCC)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[O:22][CH2:2][C:3]([CH3:4])([CH3:5])[N:6]=2)=[CH:9][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCOc1cc(C(=O)NC(C)(C)CO)ccc1OC
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCCCCOc1cc(C2=NC(C)(C)CO2)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
N-(2-Hydroxy-1,1-dimethylethyl)-4-methoxy-3-pentyloxybenzamide (5.498 g, 0.0178 mol, 1 eq) was dissolved in thionyl chloride (4.29 ml, 0.0214 mol, 3.3 eq), and the solution was stirred at room temperature for 1 hour. The reaction mixture was poured into diethyl ether (40 ml). The obtained hydrochloride compound was collected by filtration, and excess thionyl chloride was removed. A 1N aqueous sodium hydroxide solution (about 20 ml) was added to this hydrochloride compound under ice-cooling, whereby the mixture was alkalized (pH=10). The solution was extracted twice with diethyl ether (30 ml). The organic layers were combined, washed with saturated brine (60 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(4-methoxy-3-pentyloxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (4.46 g, 86%) as colorless crystals.