Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)[CH3:8])(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:26]1[N:25]=[CH:24][C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:8])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2ccc(F)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: CNC1CCC(N(Cc2cc(-c3ccc(F)nc3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(6-fluoro-pyridin-3-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(6-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 57%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[F:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)O[C@@H](CN1CCOCC1)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2R)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.39 g, 0.95 mmol), morpholine (0.3 ml, 3.4 mmol) and ACN (3 ml) was heated under microwave radiation at 120° C. for 70 min. Purification on SCX-3 column (TEA/MeOH) and by flash column chromatography and (isooctane/EtOAc/MeOH). Yield: 0.17 g. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 251° C. MS m/z (rel. intensity, 70 eV) 331 (M+, 1), 207 (2), 101 (6), 100 (bp), 69 (2), 56 (5).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH3:34])[CH2:33][O:32][CH2:31]1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2([CH3:34])[CH2:33][O:32][CH2:31]2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCC1(C)COC1
Temperature: 80 °C
Yield: 48.4 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and 3-bromomethyl-3-methyl-oxetane (138 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (50 mg, 48.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH:25]1([CH2:31][Zn+])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN1CCCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Zn+]CC1CCCCC1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN1CCCC1
Agent: [Br-]
Solvent: CCOC(C)=O
Product: c1ccc(COc2cc(CC3CCCCC3)nnc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) (1 g, 3.06 mmol) and bis(tri-tert-butylphosphine)palladium (0.063 g, 0.122 mmol) in N-methylpyrrolidine (30.0 ml) under nitrogen was added (cyclohexylmethyl)zinc(II) bromide (0.5 M in tetrahydrofuran) (12.24 ml, 6.12 mmol) and the resulting brown mixture was stirred at room temperature overnight and then heated at 100° C. for 2 hours. The reaction mixture was then allowed to cool, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and brine. The organics were dried (MgSO4), filtered and solvent removed in vacuo to give a brown oil. The oil was purified by silica chromatography (eluting with 0-30% ethyl acetate in petrol) to yield the title compound (540 mg, 1.39 mmol, 45% yield).
Reaction SMILES: [O:1]=[C:2]1[N:11]2[CH2:12][CH2:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[H-].[Na+].[CH3:17][CH2:18][CH2:19]CCC.C(Br)C=C>CC(N(C)C)=O>[O:1]=[C:2]1[N:11]2[CH2:12][CH2:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]1[CH2:19][CH:18]=[CH2:17]
Reactant: CCCCCC
Reactant: O=C1Nc2ccccc2C2=NCCN12
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: CC(=O)N(C)C
Product: C=CCN1C(=O)N2CCN=C2c2ccccc21
Temperature: 80 °C

Procedure:
6.9 g (0.037 mol) of 5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline in 60 ml of absolute dimethylacetamide were added to 1.75 g (0.058 mol) of an 80% strength suspension of NaH in oil (Schuchardt), after the suspension had been thoroughly stirred twice with 20 ml of n-hexane in each case and the solvent had been decanted, and the mixture was heated to 80° C. for 1 hour. During this process, a clear solution was gradually formed. The solution was cooled, and 4.6 ml (0.053 mol) of allyl bromide were added dropwise. The mixture was then heated to 100° C. for 4 hours. It was concentrated in a rotary evaporator to one third of its volume and was poured onto ice-water. The precipitated product was filtered off under suction and was recrystallised from methanol/water.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7](C(OC(C)(C)C)=O)[CH2:6][C:5]=2[C:4]2[CH:19]=[CH:20][C:21]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])=[N:22][C:3]1=2.C(Cl)[Cl:41]>Cl.CO.CCOCC>[ClH:41].[CH3:1][N:2]1[C:11]2[CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]=2[C:4]2[CH:19]=[CH:20][C:21]([N:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[CH:25][C:24]3=[O:39])=[N:22][C:3]1=2
Reactant: ClCCl
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CC(C(=O)OC(C)(C)C)NCC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CNCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A suspension of tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-d]azepine-6(5H)-carboxylate (149 mg, 0.276 mmol) in 1.25 M HCl in MeOH (3.0 mL) was stirred under N2 at ambient temperature for 18 h. CH2Cl2 (1.5 mL) was added to the suspension and the resulting solution was stirred at ambient temperature for 18 h. CH2Cl2 (1.0 mL) and 1.25 M HCl in MeOH (1.0 mL) were added to the solution, and the resulting solution was stirred at ambient temperature for 6 h. Additional 1.25 M HCl in MeOH (2.0 mL) was added to the solution, and the resulting solution was stirred for 18 h. The solution was diluted with Et2O, and the resulting solids were collected by filtration to afford the title compound (104 mg, 79%) as a light-yellow powder: mp 308-312° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.21 (d, J=2.0 Hz, 1H), 9.04 (s, 2H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.09-8.05 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.85 (dd, J=7.5, 2.0 Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.49-3.46 (m, 2H), 3.17-3.15 (m, 2H), 2.09-2.07 (m, 2H); ESI MS m/z 440 [M+H]+; HPLC (Method A) 98.1% (AUC), tR=13.4 min.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH:20](=[O:22])[CH3:21]>C1COCC1.Cl.O>[Cl:13][C:14]1[C:19]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccccn1
Reactant: CC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(O)c1cccnc1Cl
Temperature: -70 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Dry THF (400 mL) and n-butyllithium (1.6 M in hexane, 63 mL, 0.1 mol) were introduced into a 1 L flask under nitrogen at −70° C. A solution of dry diisopropylamine (10.1 g, 0.1 mol) in THF (25 mL) was added dropwise to the mixture at −70° C. The mixture was then kept for 1 h at 0° C. and then cooled to −70° C. A solution of 2-chloropyridine (11.3 g, 0.1 mol) in THF (25 mL) was added dropwise to the mixture at −70° C. and the mixture was stirred for 3 h at this temperature. A solution of acetaldehyde (4.85 g, 0.11 mol) in dry THF (50 mL) was then added dropwise and the mixture was kept for 3 h at −70° C. A solution of water (4 mL) in THF (40 mL), acidified by a few drops of concentrated hydrochloric acid, was added to the mixture at −40° C. and then water (200 mL) was introduced at −10° C. Extraction with diethyl ether (3×150 mL), drying over anhydrous sodium sulfate, and evaporation gave a crude product, which was purified by column chromatography to yield an oil (10 g, 64%). *1H NMR (CDCl3) 8.15 (dd, J=5 and 2 Hz, 1H), 7.95 (dd, J=8 and 2 Hz, 1H), 7.20 (dd, J=8 and 5 Hz, 1H), 5.15 (d, J=7 Hz, 1H), 3.90 (s, 1H), 1.45 (d, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]([OH:32])[CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:9]=2)[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]=2[N:4]=1)[CH3:2].C(Cl)Cl.FC(F)(F)C(O)=O>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]([CH:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)[OH:32])[N:14]3[CH3:17])=[C:10]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:9]=2)[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(O)C3CCNCC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)(hydroxy)methyl)piperidine-1-carboxylate (0.320 g, 0.555 mmol) in Methylene chloride (10 mL, 200 mmol;) was added Trifluoroacetic Acid (0.50 mL, 6.5 mmol;). The reaction was stirred at room temperature for 1 hr. and the reaction mixture was evaporated to dryness. To the residue was added 2M NH3 in MeOH to neutralize any residual acid. The mixture was then evaporated to dryness. The crude was then purified by flash chromatography (0-15% MeOH in DCM) to give the desired product as pinkish paste (0.24 g, 91%). LCMS m/z 477.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:30])([F:29])[F:28])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([OH:8])=O.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH2:44])(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:28])([F:30])[F:29])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([NH:44][S:41]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH3:34])(=[O:42])=[O:43])=[O:8]
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Yield: 56.8 %

Procedure:
A solution of 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-yl-methyl]benzoic acid (250 mg), 4-dimethylaminopyridine (69.8 mg), I-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg) and 2-methylbenzenesulfonamide (95.4 mg) in methylene chloride (5 mL) was stirred under a nitrogen atmosphere 4or 24 hours. The mixture was diluted with methylene chloride, washed (10% (w/v) hydrochloric acid, water), and evaporated. The resulting rose-colored foam was dissolved in methylene chloride (5 mL), filtered through a 0.45 micron membrane filter, and precipitated by addition to hexane (50 mL). The solid was collected by filtration to give the title compound (189.2 mg, 57%) as a pale pink powder; mp 147°-149° C. Analysis for C31H32F3N3O5S: Calculated: C, 60.48; H, 5.24; N, 6.83. Found: C, 60.39; H, 5.60; N, 6.59.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1.C(O)(=[O:16])C.[OH-].[Na+]>O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]([CH2:3][OH:16])[OH:4]
Reactant: CCCCCCCCOCC1CO1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCOCC(O)CO
Temperature: 200 °C
Reaction time: 1 h
Yield: 558 %

Procedure:
In a reactor, 390 g of octanol, 2 g of aluminum triisopropoxide and 1.4 g of sulfuric acid were charged. After heating to 100° C., dehydration was conducted under reduced pressure (2.67 kPa). The residue was then cooled to 85° C., followed by the dropwise addition of 185 g of epichlorohydrin at a temperature maintained at 85° C. After stirring at 85° C. for 4 hours, an excess alcohol was removed at 100° C. under reduced pressure (0.67 kPa). To the crude octyl halohydrin ether thus obtained, 480 g of a 209 aqueous solution of sodium hydroxide was added and the resulting mixture was reacted at 90° C. for 2 hours. After completion of the reaction, the water layer was removed, whereby 315 g of crude octyl glycidyl ether was obtained. In an autoclave, 200 g of the resulting crude octyl glycidyl ether, 35 g of water, 11.8 g of 99% acetic acid and 12.1 g of a 48% aqueous solution of sodium hydroxide were charged, followed by stirring at 200° C. for 1 hour. At a temperature maintained at 200° C., 27.5 g of a 48% aqueous solution of sodium hydroxide was added dropwise over 3 hours and reaction was conducted for 1 hour. The reaction mixture was cooled to 80° C. While maintaining the temperature at 80° C., 150 g of water was added and the resulting mixture was stirred vigorously. The reaction mixture was allowed to stand to cause separation, followed by removal of the water layer. The operation from the addition of 150 g of water to the separation was then repeated three times. The reaction mixture was dehydrated at 100° C. under reduced pressure (5.32 kPa), whereby 224 g of monooctyl glyceryl ether was obtained. As a result of GLC, it was found that the resulting product had a purity of 91% and the content of organochlorine compounds was not greater than 100 ppm.
Reaction SMILES: N[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([Br:14])=[CH:4][N:3]=1.N([O-])=[O:16].[Na+]>>[OH:16][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([Br:14])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)nc1N1CCOCC1
Reactant: O=N[O-]
Agent: [Na+]
Product: Oc1ncc(Br)nc1N1CCOCC1

Procedure:
2-Amino-3-morpholino-5-bromopyrazine (see Preparation 92, Step A) is treated with sodium nitrite by the method described in Preparation 91, Step C, to give 2-hydroxy-3-morpholino-5-bromopyrazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:22][C:21]3[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[N:17]([CH3:26])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)=[O:28].N1C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH:27]=[O:28])[C:21]3[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[N:17]([CH3:26])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 17.6 %

Procedure:
4-(1,3-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylic acid tert-butyl ester (226 mg), 2-formylphenyl boronic acid (200 mg), and copper (II) acetate (200 mg) were suspended in anhydrous tetrahydrofuran (5 ml), and pyridine (0.2 ml) was added thereto. The reaction mixture was stirred at room temperature for 5 days, filtered through a short column filled with silica gel, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 51 mg of the title compound from a fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: [Li].[C:2]([C:4]1[C:9]([CH2:10][C:11]([OH:13])=[O:12])=[C:8]([F:14])[C:7]([NH:15][CH2:16][C:17]([F:25])([F:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:6][CH:5]=1)#[N:3].[F:26][C:27]1[C:32](O)=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].Cl.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.C(N=C=NC(C)C)(C)C>CN(C)C=O.C(Cl)Cl>[F:26][C:27]1[C:32]([O:12][C:11](=[O:13])[CH2:10][C:9]2[C:4]([C:2]#[N:3])=[CH:5][CH:6]=[C:7]([NH:15][CH2:16][C:17]([F:25])([F:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:8]=2[F:14])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: N#Cc1ccc(NCC(F)(F)c2ccccn2)c(F)c1CC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(NCC(F)(F)c2ccccn2)c(F)c1CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.2 %

Procedure:
To a solution of the lithium salt of [6-cyano-3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2-fluoro-phenyl]-acetic acid (75 mg, 0.22 mmol), prepared essentially as described in Example 1k, in N,N-dimethylformamide (0.250 mL) and methylene chloride (0.750 mL) was added pentafluorophenol (121 mg, 0.66 mmol), pyridine hydrochloride (52 mg, 0.45 mmol), dimethylaminopyridine (14 mg, 0.11 mmol), and finally diisopropylcarbodiimide (0.038 mL, 0.24 mmol). The mixture was stirred at room temperature for 24 h. The solvents were evaporated under high vacuum and the residue was purified by flash column chromatography (20-30% ethyl acetate in hexanes) to yield the desired compound (51 mg, 50%). 1H-NMR (300 MHz, CDCl3) δ 8.68 (d, J=5.5 Hz, 1H), 7.84 (td, J=7.8 Hz, 1.7 Hz, 1H), 7.69 (dt, J=7.9 Hz, 1.1 Hz, 1H), 7.40-7.45 (m, 1H), 7.35 (dd, J=8.6 Hz, 1.3 Hz, 1H), 6.86 (t, J=8.5 Hz, 1H), 5.05 (br s, 1H), 4.12-4.23 (m, 4H). LC/MS (m/z) [M+1]+ 502.3 (calculated for C22H12F8N3O2, 502.3).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN1CCCC1=O>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([F:45])=[C:23]([NH:22][C:8]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[C:6]=5[CH3:7])=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1c(C(=O)O)cnn1C
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)cnn1C
Yield: 47.2 %

Procedure:
Using 1,5-dimethyl-1H-pyrazole-4-carboxylic acid (140 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (106 mg, yield 47%) was obtained.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Cl:15][CH2:16][C:17]([NH:19][CH:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21]1)=[O:18].O.Cl>O1CCCC1>[Cl:15][CH2:16][C:17]([NH:19][C@H:20]1[C@@H:29]([OH:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21]1)=[O:18]
Reactant: O=C(CCl)NC1COc2ccccc2C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCl)N[C@@H]1COc2ccccc2[C@@H]1O
Yield: 0.1 %

Procedure:
Lithium tri-sec-butylborohydride (1.0 M solution in tetrahydrofuran, 190 ml, 190 mmol) was added to a solution of 2-chloro-N-(4-oxo-chroman-3-yl)-acetamide (22.6 g, 94.3 mol) in tetrahydrofuran (1000 ml). When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-((3RS,4SR)-cis-4-hydroxychroman-3-yl)-acetamide (19 g, 78.6 mmol, 83%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:21](=[O:22])[C:20]5=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]5[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:21]([OH:22])[CH:20]5[C:19](=[CH:26][CH:25]=[CH:24][CH2:23]5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1C2=CC=CCC2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a suspension of N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide (7.8 g, 19.8 mmol) in methanol (250 ml) and DCM (30 ml) was added NaBH4 (1.7 g, 45.5 mmol) at room temperature under nitrogen. After stirring for 0.5 hours the homogeneous reaction mixture was concentrated. The remaining solid was purified on a flash chromatography column (SiO2, 1:1 EtOAc/DCM, increased to 10% MeOH) to give 7.0 g (90%) of the desired product as a solid which was recrystallized from EtOAc, m.p.=172-173° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C([O:11]/[C:12](/[C:22](OC)=[O:23])=[C:13](/OC(=O)C)\[C:14]([O:16][CH3:17])=[O:15])(=O)C.C(OC(C)C)(C)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH3:17][O:16][C:14]([C:13]1[N:7]=[C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]2[C:22](=[O:23])[C:12]=1[OH:11])=[O:15]
Reactant: Cc1cc(N)no1
Reactant: COC(=O)/C(OC(C)=O)=C(\OC(C)=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: COC(=O)c1nc2cc(C)on2c(=O)c1O
Temperature: 100 °C
Yield: 37 %

Procedure:
5-Methyl-isoxazol-3-ylamine (392 mg, 3.99 mmol), dimethyl diacetoxyfumarate (1.04 g, 3.99 mmol) and p-toluenesulphonic acid (10 mg) were combined in a capped vial and heated to 100° C. After 5 h the reaction was cooled to room temperature and ethanol (2.5 mL) and iso-propyl ether (2.5 mL) was added to the residue which was sonicated for 15 min. The resulting precipitate collected by filtration and washed with cold ethanol (5 mL) and dried on the pump to afford 6-hydroxy-2-methyl-7-oxo-7H-isoxazolo[2,3-α]pyrimidine-5-carboxylic acid methyl ester (331 mg, 37%): 1H NMR (300 MHz, D6DMSO) δ 2.50 (3H, s, CH3), 3.84 (3H, s, OCH3), 6.67 (1H, s, H3), 10.31 (1H, br s, OH).