Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC(O)=O.[C:18]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([CH3:13])=[C:2]([NH:1][CH:28]2[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 23 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1.40 g, 7.04 mmol) in CH2Cl2 (30 mL) and AcOH (2.50 g, 42.2 mmol) was added N-Boc piperidinone (1.96 g, 9.85 mmol) and sodium triacetoxyborohydride (4.40 g, 21.1 mmol). The reaction mixture was stirred at 23° C. for 18 hours and then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×20 mL) and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 heptane/ethylacetate=10/1 to 1/1) to give the titled compound as oil (2.40 g, 89% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.09 (s, 1H), 6.69 (s, 1H), 4.05 (m, 2H), 3.88 (s, 3H), 3.63 (m, 1H), 3.42 (m, 1H), 2.97 (m, 2H), 2.23 (s, 3H), 2.05 (m, 2H), 1.45 (s, 9H), 1.27 (m, 2H).
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([Br:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[BH4-].[Na+].C(OCC)(=O)C.CCCCCC>CO.Cl[Ni]Cl>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([Br:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)Oc1cc(N)c(Br)cc1C1CCCC1
Reaction time: 0.08 h
Yield: 53.8 %

Procedure:
Alternative Procedure: To a solution of 4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (100 mg, 0.29 mmol) and NiCl2 (49 mg, 0.38 mmol) in methanol (1.0 mL) was added NaBH4 (14 mg, 0.38 mmol) portion-wise at 0° C. The reaction was stirred for 5 min then quenched with NaHCO3 and diluted with ethyl acetate. The reaction mixture was filtered through a pad of Celite and the layers separated. The aqueous layer was re-extracted with ethyl acetate and the combined organic extracts were dried over Na2SO4, filtered and concentrated. Silica gel chromatography (10% ethyl acetate/hexane) provided 5-amino-4-bromo-2-cyclopentylphenyl methyl carbonate (49 mg, 54% yield).
Reaction SMILES: [CH2:1](OC1CCCCO1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14].C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14]
Reactant: BrC(Br)(Br)Br
Reactant: CCC#CCCCCCCCCCCOC1CCCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC#CCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
The alkynyl ether 16 (5.62 g, 0.0191 mol) in dichloromethane (150 ml) at 0° C. was treated successively with carbon tetrabromide (8.23 g, 0.0248 mol) and triphenylphosphine (13 g, 0.050 mol) and stirred for 5 h at r.t. The solution was treated with silica gel, the solvent removed invacuo and the dry residue loaded onto a prepared flash column. Elution with hexanes yielded the pure bromide 17 (87% from 15); δH (270 MHz, CDCl3) 1.10 (3H, t, J 7.4), 1.27-1.54 (14H, m), 1.84 (2H, quin, J 7.3), 2.15 (4H, m) and 3.40 (2H, t, J 6.8). δC (100 MHz, CDCl3) 12.82, 14.79, 27.28, 29.23, 29.26, 29.4, 29.53, 29.80, 29.80, 30.11, 33.04, 79.96 (quartenary) and 82.00 (quartenary).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[CH3:9][C:10]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH:9]=[CH2:10])=[N:6][CH:7]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Brc1cnc(I)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ncc(Br)cn1
Temperature: 80 °C

Procedure:
5-Bromo-2-iodo-pyrimidine (2.15 g, 7.55 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.60 mL, 9.43 mmol) and PdCl2(dppf). (300 mg, 0.40 mmol) were dissolved in 1,4-dioxane (15 mL). A solution of Cs2CO3 (4.91 g, 15.1 mmol) in H2O (5 mL) was added and the mixture heated at 80° C. for 30 min. The reaction mixture was diluted with EtOAc (100 mL), washed with H2O, brine and separated. The organic fraction was dried and concentrated in vacuo. Purification by chromatography on silica, eluting with 5-25% EtOAc/heptane gave i (1.10 g, 79%). MS 185.11 & 187.09 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@@:26]4(OC)[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]4)[CH:22]=[CH:23][C:24]=3[Cl:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.C([SiH](CC)CC)C>C(#N)C.ClCCl>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:26]4[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]4)[CH:22]=[CH:23][C:24]=3[Cl:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCO4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 4 h
Yield: 74 %

Procedure:
To a stirred solution of (2S,3R,4S,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (5.0 g, 9.24 mmol) in acetonitrile-dichloromethane mixture 1:1 (40 mL) was added boron trifluoride diethyletharate complex (2.34 mL, 18.48 mmol), and triethylsilane (5.95 mL, 36.9 mmol) at −5° C. After stirring for 4 h at the same temperature, the reaction was quenched with aq. saturated sodium bicarbonate solution (15 mL). The volatiles were evaporated under reduced pressure, and the resulting mixture was extracted with dichloromethane (2×30 mL). The organic layers were combined and washed with brine (10 mL), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (3.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]2[NH:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=1)(=[O:18])=[O:17].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.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:27]1[CH2:26][CH2:25][O:24][C:23]2[CH:28]=[C:19]([S:16]([NH:15][C:11]3[S:10][CH:14]=[CH:13][N:12]=3)(=[O:18])=[O:17])[CH:20]=[CH:21][C:22]1=2
Reactant: COc1ccccc1Br
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
A microwave vial was charged with 1-bromo-2-methoxybenzene (0.056 ml, 0.454 mmol), N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.090 g, 0.303 mmol), Xantphos (0.035 g, 0.061 mmol), Pd2(dba)3 (0.028 g, 0.030 mmol) and sodium tert-butoxide (0.087 g, 0.908 mmol). The mixture was diluted with toluene (3.03 ml), and purged with nitrogen, and stirred at 130° C. in the microwave for 15 minutes, until clean conversion to the desired product. The reaction was filtered over a plug of Celite, washing well with DCM. The filtrate was concentrated in vacuo and further purified using a 2-g SCX column (product eluted with methanol wash). The crude material was concentrated and absorbed directly onto a 12-g RediSep Gold column and purified by silica-gel chromatography, eluting with a gradient of 0% to 100% ethyl acetate in heptanes to provide 4-(2-methoxyphenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.59-3.65 (m, 2 H) 3.74 (s, 3 H) 4.29 (t, J=4.35 Hz, 2 H) 6.16 (d, J=8.41 Hz, 1 H) 6.76 (d, J=4.60 Hz, 1 H) 7.00-7.04 (m, 1 H) 7.04-7.11 (m, 2H) 7.17 (dd, J=8.31, 1.27 Hz, 1 H) 7.21 (d, J=4.60 Hz, 1 H) 7.28 (dd, J=7.78, 1.61 Hz, 1 H) 7.31-7.37 (m, 1 H) 12.52 (br. s., 1 H). m/z (ESI) 404.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([CH2:9][C@@H:10]2[C@H:13]([NH:14][C:15](=[O:31])/[C:16](=[N:23]\[O:24][C:25]3([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]3)/[C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[C:12](=[O:32])[N:11]2[S:33]([OH:36])(=[O:35])=[O:34])[CH2:4]1.Cl.[N:38]1([C:43](N)=[NH:44])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:19]1[S:20][CH:21]=[C:17](/[C:16](=[N:23]/[O:24][C:25]2([C:28]([OH:30])=[O:29])[CH2:26][CH2:27]2)/[C:15]([NH:14][C@@H:13]2[C:12](=[O:32])[N:11]([S:33]([OH:36])(=[O:34])=[O:35])[C@@H:10]2[CH2:9][N:5]2[CH2:4][C@@H:3]([CH2:2][NH:1][C:43]([NH2:44])=[NH:38])[O:7][C:6]2=[O:8])=[O:31])[N:18]=1
Reactant: N=C(N)n1cccn1
Reactant: NC[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NC[C@@H]1CN(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)C(=O)O1
Temperature: 25 °C
Reaction time: 19 h
Yield: 37.8 %

Procedure:
To a solution of 1-(((Z)-(2-(((2R,3S)-2-(((R)-5-(aminomethyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropane-carboxylic acid (0.795 mmol) and Pyrazole-1-carboxamidine hydrochloride (234.8 mg, 1.602 mmol) in DMF (7.0 mL) was added DIPEA (1.20 mL, 8.06 mmol). After 19 h of stirring at rt, the solution was concd in vacuo and purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (177 mg, 37%) as a white powder. LCMS: Rt=0.47 min, m/z=590.1 (M+H) Method 2m_acidic_polar; 1H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J=8.9 Hz, 1H), 7.62 (br s, 1H), 7.24 (s, 3H), 6.81 (s, 1H), 5.23 (dd, J=8.9, 5.9 Hz, 1H), 4.60-4.51 (m, 1H), 4.23 (ddd, J=9.0, 5.8, 3.7 Hz, 1H), 3.70 (t, J=8.8 Hz, 1H), 3.52 (dd, J=8.8, 5.4 Hz, 1H), 3.49-3.44 (m, 1H), 3.43-3.34 (m, 3H), 1.38-1.24 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[N:10]=1.[Cl:14][CH2:15][C:16]([N:18]=[C:19]=[O:20])=[O:17]>ClCCl.CN(C)C=O.C(N(CC)CC)C>[Cl:14][CH2:15][C:16]([NH:18][C:19]([O:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[N:10]=1)=[O:20])=[O:17]
Reactant: OCCSc1ccc2nccn2n1
Reactant: O=C=NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CCl)NC(=O)OCCSc1ccc2nccn2n1
Temperature: -20 °C

Procedure:
In a mixture of 30 ml of dichloromethane and 10 ml of dimethylformamide is dissolved 500 mg of 6-(2-hydroxyethylthio)imidazo[1,2-b]pyridazine, followed by addition of 2 drops of triethylamine. Then, with stirring and cooling at -20° C., 490 mg of chloroacetyl isocyanate is added dropwise. Thereafter, the mixture is stirred at -20° to -10° C. for 1 hour. The dichloromethane is distilled off under reduced pressure and the residual solution is subjected to silica gel (100 g) column chromatography, with elution being carried out with ethyl acetate. The eluate is concentrated under reduced pressure. To the solid residue is added 5 ml of water and after stirring, the crystals are collected by filtration. The crystals are washed with 5 ml each of water and ether and dried. The above procedure yields 6-[2-(N-chloroacetylcarbamoyloxy)ethylthio]imidazo[1,2-b]pyridazine as crystals melting at 190° to 195° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:19]([O:21][CH2:22][CH3:23])=[CH2:20])CCC>[Cl-].C([N+](CC)(CC)CC)C.CC#N.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>[Cl:1][C:2]1[C:3]([C:19]([O:21][CH2:22][CH3:23])=[CH2:20])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: C=C(OCC)c1ncc(C(=O)OCC)cc1Cl
Temperature: 80 °C

Procedure:
To a suspension of ethyl 5,6-dichloronicotinate (5.26 g, 23.90 mmol) and tetraethylammonium-chloride (11.88 g, 71.7 mmol) in MeCN (50 mL) was added tributyl(1-ethoxyvinyl)stannane (9.50 g, 26.3 mmol) and PdCl2(PPh3)2 (0.671 g, 0.956 mmol). The reaction was sealed, heated at 80° C. for 5 hours. A dark color clear solution resulted. The reaction mixture was then cooled to 20° C., concentrated and diluted with EtOAc (200 mL), and washed with water (50 mL) and brine (50 mL). The organic was then dried (Na2SO4) and concentrated to give crude ethyl 5-chloro-6-(1-ethoxyvinyl)nicotinate. The residue was then dissolved in THF (100 mL) and HCl (20 mL, 3M in H2O) was added. The reaction mixture was stirred at 20° C. for 5 hours, and saturated NaHCO3 solution was added until pH=8. The mixture was then diluted with EtOAc (200 mL) and water (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organics was washed with brine (20 mL), dried (Na2SO4) and concentrated to afford the desired product (3.56 g). LCMS m/z 228.5 (M+H)+, Rt 0.83 min.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[NH2:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:32]>CN(C=O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([C:31](=[O:32])[CH2:30][NH:29][C:10]([CH:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]2)=[O:12])=[CH:38][CH:37]=1
Reactant: NCC(=O)c1ccc(F)cc1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a 22-L flask is added 526.4 g (3.07 mol) of 1-acetylpiperidine-4-carboxylic acid, 8 L of methylene chloride, and 55 mL of DMF. To the resultant heterogeneous suspension is added 508.9 g (3.13 mol) of carbonyl diimidazole in two portions at room temperature. After two hours, 583.5 g (3.07 mol) of 2-Amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (J. Heterocylcic Chem (1987), 24, 297. ) is added and the resultant mixture is allowed to stir overnight. The reaction mixture is extracted with 2 N HCl (3×1 L), saturated sodium bicarbonate solution (3×1 L), brine (1×1 L), dried over sodium sulfate, and filtered. To the filtrate is added toluene and the solution is concentrated in-vacuo to ca. 100 mL and the resultant precipitate is filtered. The solid is dried in-vacuo at 60° C. for 18 h to give 800 g of 1-Acetyl-piperidine-4-carboxylic acid[2-(4-fluoro-phenyl)-2-oxo-ethyl]-amide as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].Cl[C:13]1[N:18]=[C:17]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[N:20]2)[C:16]([Cl:28])=[CH:15][N:14]=1>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[N:20]3)[C:16]([Cl:28])=[CH:15][N:14]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: Clc1ncc(Cl)c(-n2nnc3ccccc32)n1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Solvent: C1CCOC1
Product: COC(=O)C1CCC(Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
trans-4-Amino-cyclohexanecarboxylic acid methyl ester (727 mg, 3.76 mmol) was added in portions, at RT under nitrogen atmosphere, to a solution of 1-(2,5-dichloro-pyrimidin-4-yl)-1H-benzotriazole (500 mg, 1.88 mmol) in THF (50 mL) followed by TEA (0.79 mL, 5.64 mmol). The resultant white suspension was stirred at RT overnight, and then at 60° C. for 2.5 days. The mixture was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated, washed twice with water (100 mL) and once with brine (100 mL), then dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to give an off-white solid. This crude material was purified via flash chromatography (toluene/EtOAc, 90/10) to afford 538 mg (74% yield) of 4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexanecarboxylic acid methyl ester as an off-white solid. MS: 387.10 (M+1)+, 359.13 ((M+1)+−28).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[C:1]([O:5][C:6](=[O:32])[CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:34][N:35]3[C:39](=[O:40])[C:38]4[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:36]3=[O:45])=[C:17]([C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)[CH:16]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)(C)OC(=O)C=Cc1ccc(-c2ccc(OCN3C(=O)c4ccccc4C3=O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Yield: 55 %

Procedure:
A solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)acrylic acid tert-butyl ester (200 mg, 0.464 mmol), N-chloromethylphthalimide (91 mg, 0.464 mmol), K2CO3 (70 mg, 0.464 mmol) and NaI (70 mg, 0.464 mmol) was stirred overnight at RT in the dark. The solvent was evaporated and the residue was taken up in EtOAc. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. 3-[3′-Adamantan-1-yl-4′-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethoxy)-biphenyl-4-yl]acrylic acid tert-butyl ester was obtained after purification on silica gel (EtOAc/hexane 15:85) in 55% yield (150 mg).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([CH3:19])([CH3:18])[O:15][C:16](=[O:17])[C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=2)=[CH:25][CH:24]=1>>[CH3:19][C:14]1([CH3:18])[O:13][C:12]2[CH:20]=[CH:21][C:9]([CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:35](=[O:37])[C:34]3[CH:33]=[CH:32][C:31]([C:30]#[C:29][C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=4)=[CH:39][CH:38]=3)=[CH:10][C:11]=2[C:16](=[O:17])[O:15]1
Reactant: O=C(O)c1ccc(C#Cc2ccc(F)cc2)cc1
Reactant: CCCCCCNCc1ccc2c(c1)C(=O)OC(C)(C)O2
Product: CCCCCCN(Cc1ccc2c(c1)C(=O)OC(C)(C)O2)C(=O)c1ccc(C#Cc2ccc(F)cc2)cc1
Yield: 98.5 %

Procedure:
The title compound was prepared following procedure described in example 20, step e) from 6-[(hexylamino)methyl]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (490 mg, 1.68 mmol) and 4-[(4-fluorophenyl)ethynyl]benzoic acid (484 mg, 2.02 mmol). Purification of the crude product by flash chromatography on silicagel (EtOAc/c-Hex (20/80) gave 850 mg (98%) of the title compound. HPLC, Rt: 5.54 min (purity: 99.9%). LC/MS, M+(ESI): 514.1. 1H NMR (CDCl3) δ: 7.45-7.90 (m, 6H), 7.37 (d, J=8.1 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H), 6.94 (d, J=8.5 Hz, 1H), 4.69 (s, 1.5H), 4.45 (s, 0.5H), 3.39 (s, 0.5H), 3.14 (s, 1.5H), 1.07-1.77 (m, 14H), 0.80 (m, 3H).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([O:18]C)=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21].[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21]
Reactant: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 1 h
Yield: 74.9 %

Procedure:
5.3 g (18 mmol) of methyl ester (6) obtained in Example 2 (1) was added to 250 ml of tetrahydrofuran, and, while the solution was heated under reflux, 100 ml of aqueous solution containing 0.76 g (19 mmol) of sodium hydroxide was added to the solution. The obtained solution was heated under reflux for 1.5 hours. After air-cooled, while cooling on ice, the solution was neutralized with 4.2 g (20 mmol) of citric hydrate and stirred for 1 hour. The solid was filtered off and washed consecutively with water, ethanol and ether to obtain 3.78 g of the subject compound (8) in a 75% yield. The result of the analysis of this compound was as follows.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:20])[C:13]([C:18]#[N:19])=[CH:14][NH:15]2)=[CH:10][C:9]=1[O:21][CH3:22]>C(O)(=O)C>[CH3:22][O:21][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:8]=1[O:6][CH2:5][CH2:4][O:3][CH3:2])[NH:15][CH:14]=[C:13]([C:18]#[N:19])[C:12]2=[O:20]
Reactant: COc1cc2c(=O)c(C#N)c[nH]c2cc1F
Reactant: COCCO
Agent: [Na]
Solvent: CC(=O)O
Product: COCCOc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium (84 mg, 3.67 mmol) is added to 3.6 mL of 2-methoxyethanol and the mixture is heated at reflux for 90 minutes. 7-Fluoro-6-methoxy-4-oxo-1,4,-dihydro-3-quinolinecarbonitrile (200 mg, 0.92 mmol) is added and the reaction mixture is heated at reflux for 4 hours then stirred at room temperature overnight. The reaction mixture is poured into ice water and acidified with acetic acid. The solids are collected by filtration, washing with ethyl acetate and hexane, to provide 234 mg of 6-methoxy-7-(2-methoxyethoxy)-4-oxo-1,4,-dihydro-3-quinolinecarbonitrile, mp>300° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[N:14]1([CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26]([CH:31]=O)=[CH:25]3)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[O:1]=[C:2]1[C:10](=[CH:31][C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:21][CH2:20][CH2:19][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:30][CH:29]=3)[C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Product: O=C1Nc2cc(C(=O)O)ccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:19])[CH3:18]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:18][C:17](=[O:19])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cc1ccc(OCc2ccccc2)cc1
Yield: 79.9 %

Procedure:
A solution of 10.0 g of p-benzyloxybenzaldehyde and 15.7 g of acetylmethylenetriphenylphosphorane in 100 ml of toluene was heated under reflux for 2 hours, the solvent was then evaporated and the residual crystals were recrystallized from ether to give 9.5 g of the desired compound melting at 106°-107° C.