Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:34])=[C:25]([CH:33]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:22]2[C:21]([Cl:20])=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[C:24]([F:34])[CH:23]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To solution of (1-benzhydrylazetidin-3-yl)methanol (368 mg) and tert-butyl 5-chloro-2,4-difluoro-benzoate (397 mg) in DMSO (7.3 mL) at 14° C. (bath) was added potassium tert-butoxide (196 mg). The mixture was stirred at rt for 1 hr. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (2×) and brine (1×), dried (Na2SO4). After filtration and concentration, the crude was purified with flash chromatography (0-40% EtOAc/heptane) to give the product (511 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[C:19]#[N:20].[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[NH:24][CH2:23]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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].C1(C)C=CC=CC=1>[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[N:24]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[C:19]#[N:20])[CH2:23]1
Reactant: N#Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC1(C)CN(c2c(C#N)c(-c3ccccn3)nc3cc(F)ccc23)c2cc(N3CCOCC3)cnc21
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 4-chloro-7-fluoro-2-(pyridin-2-yl)quinoline-3-carbonitrile (30 mg, 0.11 mmol) (described herein), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-6-yl)morpholine (30 mg, 0.13 mmol) (described herein), sodium tert-butoxide (30.5 mg, 0.32 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (15.12 mg, 0.032 mmol), Pd2dba3 (14.53 mg, 0.016 mmol), and toluene (1.0 mL) was stirred at 105° C. for 3 h, then cooled to rt and concentrated. The resulting residue was taken up in EtOAc, washed with saturated aqueous sodium bicarbonate solution, 1M NaOH, and brine, and the organic layer dried (MgSO4) and concentrated. Chromatography afforded 4-(3,3-dimethyl-6-morpholino-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-2-(pyridin-2-yl)quinoline-3-carbonitrile as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.83 (1H, ddd, J=4.8, 1.7, 0.9 Hz), 8.19-8.31 (1H, m), 7.82-8.01 (3H, m), 7.72-7.82 (1H, m), 7.42-7.57 (1H, m), 7.28-7.37 (1H, m), 6.05-6.21 (1H, m), 4.60-4.72 (1H, m), 3.83-3.94 (1H, m), 3.70-3.83 (4H, m), 2.90-3.11 (4H, m), 1.55-1.62 (3H, m), 1.48-1.55 (3H, m). Mass Spectrum (ESI) m/e=481 (M+1).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:2]1[C:9]#[N:10].N1C=CC=CC=1.[FH:17].C(OCC)(=O)C>ClCCl>[F:17][C:3]1([CH:2]([OH:1])[C:9]#[N:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: F
Reactant: N#CC1OC12CCOCC2
Agent: *CC(*)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC(O)C1(F)CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 1,6-dioxaspiro[2,5]octane-2-carbonitrile (4.14 g, 29.8 mmol) in dry dichloromethane (10 mL) and cool to 0° C. under a nitrogen atmosphere in a polypropylene bottle. Add hydrogen fluoride-pyridine (3 mL) dropwise. Allow the mixture to slowly warm to room temperature over 3 h and then stir an additional 1.5 hours at room temperature. Pour into ethyl acetate and wash with saturated aqueous sodium bicarbonate solution until washes remain basic. Combine the aqueous washes and adjust the pH of the solution to ˜pH=8 and extract with ethyl acetate. Combine this organic extract with the ethyl acetate solution of the crude reaction mixture and wash with saturated aqueous sodium chloride solution, dry (magnesium sulfate), filter and concentrate to give the desired compound as a yellow oil which is used directly in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[C:32]([CH3:33])=[C:31](I)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH:23][C:31]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:24])[C:32]=1[CH3:33])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C)[C@@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 110 °C
Yield: 99 %

Procedure:
To a solution of 61F (325 mg, 0.94 mmol) in degassed toluene:DMSO (2:1, 7 mL) at rt was added 61G (260 mg, 0.94 mmol), Cs2CO3 (614 mg, 1.89 mmol) and a solution of Pd2(dba)3 and (S)—N,N-dimethyl-1-[(R)-2-(diphenyphosphino)ferrocenyl]ethylamine (1:6 ratio, 0.06 mol %) in nitrogen degassed toluene (3 mL). The reaction was degassed with nitrogen for 30 min, sealed and heated at 110° C. for 48 h. Cool to rt and extract with EtOAc (50 mL) and wash with water followed by sat'd aqueous NaHCO3. Dry over MgSO4, filter and concentrate. Purification by flash chromatography (40 g ISCO silica gel cartridge, 0-10% EtOAc in hexane gradient) gave the title compound (460 mg): MS (ES) m/z 494.29 [M+H]+
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](OB([O-])[O-])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[C:16]1[CH:17]=[CH:18][C:19]2[N:25]([CH3:26])[CH2:24][CH2:23][C:22]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH3:44])[CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:32][CH:31]=3)=[O:28])=[CH:21][C:20]=2[CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:16]3[CH:17]=[CH:18][C:19]4[N:25]([CH3:26])[CH2:24][CH2:23][C:22]([C:27]([NH:29][C:30]5[CH:31]=[CH:32][C:33]([CH2:36][N:37]([CH3:44])[CH:38]6[CH2:43][CH2:42][O:41][CH2:40][CH2:39]6)=[CH:34][CH:35]=5)=[O:28])=[CH:21][C:20]=4[CH:45]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCCO2
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc4c(c3)OCCO4)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved (2,3-dihydro-1,4-benzodioxin-6-yl)borate (221 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (397 mg). To the solution was added potassium carbonate (272 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (38 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (35 g, ethyl acetate:ethanol=20:1) and recrystallized from ethanol to give 7-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 24) (215 mg, 49%) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:21][O:20][N:19]([CH3:18])[C:14]([C:8]1([C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[O:16]
Reactant: Cc1ncc(C2(C(=O)O)CCOCC2)cn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1(c2cnc(C)nc2)CCOCC1
Yield: 62.8 %

Procedure:
A solution of 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxylic acid (4.0 g, 18.02 mmol), N,O-dimethylhydroxylamine hydrochloride (2.1 g, 21.6 mmol), HOBt (2.92 g, 21.6 mmol), EDCI.HCl (4.15 g, 21.62 mmol) and DIPEA (15.6 mL, 90.1 mmol) in DMF (50 mL) was stirred at room temperature overnight. To the reaction mixture was added water and extracted with EtOAc (3×200 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude product, which was purified by flash column chromatography (EtOAc:petroleum ether=1:1) to give N-methoxy-N-methyl-4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxamide (3.0 g, yield: 63%). 1H NMR (CDCl3 400 MHz): δ8.55 (s, 2H), 3.90-3.75 (m, 4H), 3.14 (s, 3H), 2.95 (s, 3H), 2.72 (s, 3H), 2.55-2.45 (m, 2H), 2.06-1.95 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[NH:27][C:26]5[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=5[CH:20]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:3]1>C(=O)=O.C(NCC)C.N1C=CC=CC=1C(N)=O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[NH:27][C:26]5[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=5[CH:20]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:3]1
Reactant: N[C@H]1CCC[C@H](Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Agent: NC(=O)c1ccccn1
Agent: O=C=O
Solvent: CCNCC
Product: N[C@@H]1CCC[C@H](Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1

Procedure:
A solution of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 101 mg, 0.339 mmol) and cyclohexane-1,3-diamine (Aldich; 0.204 mL, 1.696 mmol) in DMSO (0.6 mL) was stirred under argon at 100° C. for 1 d. The mixture was cooled to 25° C., diluted with DMSO (1.8 mL), and purified by revered-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) to provide 2-(2-((3-aminocyclohexyl)amino)-quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (159.8 mg, 0.326 mmol, 96% yield) as a yellow-brown solid: m/z (ESI, +ve) 376.3 (M+H)+. Separation of this material by supercritical-fluid chromatography (Chiralcel OD-H (150×21 mm, 5 μm), 60% liquid CO2/40% MeOH (+0.2% diethylamine), 75 mL/min, followed by repurification of 122 by Princeton Chromatography pyridine amide column (250×21 mm, 5 μm), 70% liquid CO2/30% MeOH (+0.2% diethylamine), 75 mL/min) separately afforded rac-2-(2-((trans-3-aminocyclohexyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (120; 4.5 mg, 0.012 mmol) as a light-yellow solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 7.94 (1H, dd, J=7.5, 1.1 Hz), 7.84 (1H, d, J=9.0 Hz), 7.46 (1H, dd, J=7.7, 0.9 Hz), 7.20 (1H, t, J=7.6 Hz), 7.03 (1H, s), 6.87 (1H, d, J=9.0 Hz), 4.39 (1H, br. s.), 3.62 (2H, t, J=7.0 Hz), 3.14 (1H, t, J=9.9 Hz), 3.02 (2H, td, J=7.0, 2.6 Hz), 2.34 (1H, d, J=13.7 Hz), 1.89-2.01 (2H, m), 1.74-1.85 (3H, m), 1.58-1.68 (1H, m), 1.31-1.41 (1H, m). m/z (ESI, +ve) 376.3 (M+H)+:
Reaction SMILES: [CH:1]12[NH:16][CH:5]([CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]1)[CH2:4][O:3][CH2:2]2.[CH3:17][C:18]1[C:26]2[CH2:25][O:24][C:23](=[O:27])[C:22]=2[CH:21]=[CH:20][C:19]=1[C@@H:28]1[CH2:30][O:29]1>C(O)C>[OH:29][C@H:28]([C:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:27])[O:24][CH2:25][C:26]=2[C:18]=1[CH3:17])[CH2:30][N:16]1[CH:1]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:6][CH:5]1[CH2:4][O:3][CH2:2]2
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Solvent: CCO
Product: Cc1c([C@@H](O)CN2C3COCC2CN(C(=O)OC(C)(C)C)C3)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
Commercially available tert-Butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (300 mg, 1.3 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (INTERMEDIATE 2) (380 mg, 2.0 mmol) were dissolved in ethanol (10 ml) and heated in a microwave reactor at 140° C. for 1 hour. The reaction was concentrated and purified by MPLC on ISCO RediSep® purification column and eluted with 50%-100% ethyl acetate/hexane to provide tert-butyl 9-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]([CH3:18])=[N:9]1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[CH3:18][C:10]1[C:11]([CH2:13][C:14]([F:16])([F:15])[F:17])=[CH:12][NH:8][N:9]=1
Reactant: Cc1nn(Cc2ccccc2)cc1CC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1n[nH]cc1CC(F)(F)F
Yield: 51 %

Procedure:
To a solution of 1-benzyl-3-methyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole (compound 314.5, 700 mg, 2.75 mmol) in methanol (10 mL) was added palladium on carbon (700 mg, 10 wt. %) and HCl (4 M) (3 mL). The reaction mixture was hydrogenated for 48 h at room temperature under 1 atmosphere of hydrogen. The solids were removed via filtration. The filtrate was evaporated under reduced pressure and diluted with 50 mL of water. The pH of the solution was adjusted to 7 with NaOH (2 M). The aqueous phase was extracted with 5×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 230 mg (51%) of the title compound as a light yellow oil.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]([O:16][CH2:17][CH:18]=[CH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[CH2:9]([O:16][CH2:17][CH:18]1[CH2:19][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCOCc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)C1CC1COCc1ccccc1
Reaction time: 16 h

Procedure:
31.2 g of ethyl diazoacetate are added to a solution of 0.3 mol of allyl benzyl ether in 150 ml of ether with the aid of a push-syringe. After stirring for 16 hours, 31.2 g of ethyl diazoacetate are added again. After 24 hours the mixture is filtered. The organic phase is washed with saturated NaHCO3 solution and then treated in customary manner. Chromatography over silica gel (dichloromethane) allows the expected product to be obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=2)[CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: COc1ccc(Br)cc1C
Product: COc1ccc(-c2cc(Cl)c3ccccc3n2)cc1C

Procedure:
The title compound, m. p. 90-92° C., MS: m/e=283 (M+), was prepared from 4-chloro-quinoline and 4-bromo-1-methoxy-2-methyl-benzene.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1)[CH3:10]>>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=1
Reactant: CCc1ccc(CCO)cc1
Reactant: BrCCCCCCBr
Product: CCc1ccc(CCOCCCCCCBr)cc1

Procedure:
(2.6 g), T.l.c. [B] Rf 0.25, from 1,6-dibromohexane (9.8 g) and 4-ethylbenzeneethanol (2.0 g).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:17][C@@H:16]([N:18]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:19]3[N:24]=[CH:23][C:22]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)=[CH:21][N:20]=3)[CH2:15][C@H:14]2[CH2:46][CH3:47])=[O:12])=CC=1)([O-])=O.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>>[F:43][C:42]([F:44])([F:45])[C:34]1[CH:33]=[C:32]([CH:37]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:35]=1)[CH2:31][N:18]([C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:21][N:20]=1)[C@@H:16]1[CH2:17][N:13]([C:11]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:12])[C@H:14]([CH2:46][CH3:47])[CH2:15]1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)N1CCOCC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 73.6 %

Procedure:
A mixture of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 4-nitro-phenyl ester (0.1 mmol; 66 mg) and morpholine (1.15 mmol; 1.00 g) is stirred for 20 hours at 80° C. The reaction mixture is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give ((2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-morpholin-4-yl-methanone (45 mg; 73%) %); ESI-MS m/z: 612 [M+1]+, Retention time 2.07 min (condition A).
Reaction SMILES: FC(F)(F)C(O)=O.[ClH:8].[Cl:9][C:10]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[C:11]=1[O:12][C:13]1[CH:29]=[CH:28][C:16]2[N:17]([CH3:27])[C:18](=[O:26])[C:19]([C:22](=[O:25])[CH2:23]O)([CH3:21])[O:20][C:15]=2[CH:14]=1>ClCCl>[Cl:9][C:10]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[C:11]=1[O:12][C:13]1[CH:29]=[CH:28][C:16]2[N:17]([CH3:27])[C:18](=[O:26])[C:19]([C:22](=[O:25])[CH2:23][Cl:8])([CH3:21])[O:20][C:15]=2[CH:14]=1
Reactant: CN1C(=O)C(C)(C(=O)CO)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21
Reactant: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C(C)(C(=O)CCl)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21

Procedure:
In Example 15, dichloromethane was used as the solvent, and trifluoroacetic acid or conc. hydrochloric acid was used in place of hydroiodic acid, and 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-hydroxyacetyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 95) and 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-chloroacetyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 97) were obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:10]([N:17]1[CH:21]=[CH:20]N=C1)(N1C=CN=C1)=[O:11]>>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:17][CH2:21][CH2:20][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: NCCC1=CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCC1=CCCCC1)NCCC1=CCCCC1
Yield: 54 %

Procedure:
In the manner of step (a) of Example 6, 2-(1-cyclohexenyl)ethylamine (Aldrich, 94.6 g, 0.733 mole as 97%) was reacted with 1,1'-carbonyldiimidazole to give 1,3-bis[2-(1-cyclohexen-1-yl)ethyl]urea as a white powder (56.26 g, 54%), m.p. 129°-131° C.;
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:33])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])[CH3:2].O1CCCC1.[OH-].[Li+].O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:33])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)O)cc2)n1
Yield: 94.4 %

Procedure:
1.1 g (2.4 mmol) of methyl 2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}propanoate, 20 ml of tetrahydrofuran and 3.6 ml (3.6 mmol) of aqueous 1M lithium hydroxide solution are stirred at room temperature for 5 hours. After addition of water and ethyl acetate, the reaction medium is acidified to pH 5.5 with aqueous 1N acetic acid solution. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. 1 g (95%) of 2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}propanoic acid is obtained in the form of a viscous syrup.
Reaction SMILES: [NH2:1][CH:2]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26]Cl)[CH:20]=1)[C:3]([NH:5][CH:6]1[C:13](=[O:14])[N:12]2[CH:7]1[S:8][CH2:9][C:10]([CH3:18])=[C:11]2[C:15]([OH:17])=[O:16])=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+]>O1CCCC1>[NH2:1][CH:2]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][N:28]=[N+:29]=[N-:30])[CH:20]=1)[C:3]([NH:5][CH:6]1[C:13](=[O:14])[N:12]2[CH:7]1[S:8][CH2:9][C:10]([CH3:18])=[C:11]2[C:15]([OH:17])=[O:16])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(O)c(CCl)c3)C2SC1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(O)c(CN=[N+]=[N-])c3)C2SC1
Reaction time: 3 h

Procedure:
7-[[Amino[3-(chloromethyl)-4-hydroxyphenyl]acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.02 mole) is added to tetrahydrofuran at about 40° C. Sodium azide (0.04 mole) in tetrahydrofuran is added and the resulting mixture is stirred for 3 hours. The tetrahydrofuran is evaporated and the residue is treated with water to remove the sodium chloride and the excess sodium azide. The resulting residue is taken up in ethyl acetate and the ethyl acetate is dried over magnesium sulfate. Filtration removes the magnesium sulfate and removal of the ethyl acetate gives the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([Sn](C)(C)C)[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][N:4]=1.[C:18]1([CH2:24][CH2:25][C:26](Cl)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:26](=[O:27])[CH2:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1[Sn](C)(C)C
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(SC)nc1C(=O)CCc1ccccc1
Temperature: 100 °C

Procedure:
To a solution of Example 6A (600 mg, 1.74 mmol) in toluene (20 ml) was added palladium tetrakis(triphenylphosphine) (96 mg, 0.08 mmol) and 3-phenylpropanoyl chloride (0.37 ml, 2.5 mmol). The reaction mixture was purged with nitrogen and heated at 100° C. for 12 hours. After cooling, the reaction mixture was directly separated by flash chromatography which was eluted with 15% ethyl acetate in hexane to provide the title compound. MS (DCI/NH3) m/z 303 (M+H)+.