Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.[CH:24]([NH:27][NH2:28])([CH3:26])[CH3:25].Cl.[CH3:30][CH2:31][OH:32]>>[CH:24]([N:27]1[C:16]([C:11]2[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:17][CH:18]=[N:19]1)([CH3:26])[CH3:25].[CH:24]([N:27]1[CH:14]=[CH:15][C:10]([C:11]2[CH:16]=[CH:17][C:30]([CH2:31][OH:32])=[CH:13][N:12]=2)=[N:28]1)([CH3:26])[CH3:25]
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)NN
Reactant: CCO
Agent: Cl
Product: CC(C)n1ccc(-c2ccc(CO)cn2)n1
Product: CC(C)n1nccc1-c1ncccc1CO
Temperature: 80 °C
Yield: 25 %
Yield: 71 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude, 1.03 g, 3.22 mmol, 1 eq.; INT-1) in EtOH (10 mL) was added isopropylhydrazine hydrochloride (430 mg, 3.86 mmol, 1.2 eq.). The mixture was heated at 80° C. for 2 h, cooled, added HCl (6 N, 0.5 mL), and stirred 0/N. The mixture was concentrated and diluted with EtOAc (80 mL) and NaHCO3(sat) (10 mL) solution. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using EtOAc as eluent to give (2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (500 mg, 71%) and (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol (55 mg, 25%) as pale yellow oils. Data for 2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol: NMR (400 MHz, CDCl3) δ 8.67 (dd, J=4.7, 1.5 Hz, 1H), 8.0 (d, J=7.8 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.39 (dd, J=7.8, 4.8 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 4.67 (s, 2H), 4.55 (sep, J=6.6 Hz 1H), 1.98-2.05 (br, 1H), 1.47 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 218.1 Data for (2-(1-isopropyl-1H-pyrazol-3-yl)pyridin-5-yl)methanol: 1H NMR (400 MHz, CDCl3) δ 8.62 (dd, J=4.8, 1.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.23 (dd, J=7.6, 4.8 Hz, 1H), 6.99 (dd, J=8.0, 6.5 Hz, 1H), 6.07 (t, J=7.6 Hz, 1H), 4.67 (d, J=7.6 Hz, 2H), 4.58 (sep, J=6.7 Hz, 1H), 1.60 (d, J=6.7 Hz, 1H). MS (ESI) m/z 218.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[C:9]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]3[O:42][CH:41]=[CH:40][C:39]=3[CH:43]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[O:42]1[C:38]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:12](=[O:13])[NH:11][N:10]=[C:9]4[CH2:14][C@@H:15]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]4)=[CH:4][CH:3]=3)=[CH:43][C:39]=2[CH:40]=[CH:41]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Temperature: 100 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
In a sealed pressure tube, a mixture of 1,1-dimethylethyl (3S)-3-{[4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-1-pyrrolidinecarboxylate (2.5 g, 5.91 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (1.514 g, 6.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.241 g, 0.295 mmol), and sodium bicarbonate (1.488 g, 17.72 mmol) in 1,4-dioxane (30 mL) and water (15 mL) was stirred at 100° C. for 24 h. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (300 mL) and water (100 mL), and the layers were separated. The aqueous layer was acidified to pH˜6 using a 1N aq HCl solution and then extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF280, SF40-115g, Solvent A: ethyl acetate; Solvent B: 10% methanol/dichloromethane; Gradient: 100% A for 10 min, then 0-50% B/A over 20 min) provided the title compound as a tan solid (2.6 g, 96%). MS(ES)+ m/e 461.4 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:5][CH:4]=1)=O.[NH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][O:28][C:29]2=[O:34].[O-]S([O-])(=O)=O.[Mg+2]>CC#N>[O:34]=[C:29]1[C:30]2[C:26](=[C:25](/[N:24]=[CH:1]/[C:3]3[CH:4]=[CH:5][C:6]([CH:9]4[CH2:13][CH2:12][CH2:11][N:10]4[C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])=[CH:7][CH:8]=3)[CH:33]=[CH:32][CH:31]=2)[CH2:27][O:28]1
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccc(C4CCCN4C(=O)OCc4ccccc4)cc3)cccc21
Temperature: 120 °C
Yield: 39.7 %

Procedure:
A mixture of benzyl 2-(4-formylphenyl)pyrrolidine-1-carboxylate (0.62 g, 2 mmol), 4-aminoisobenzofuran-1(3H)-one (0.298 g, 2 mmol), MgSO4 (2.4 g, 20 mmol) in CH3CN (20 mL) was refluxed at 120° C. for 4 days. After a hot filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography (EtOAc:DCM:hexane=1:1:6) to give the title compound (0.35 g, yield 30%) as a white solid. LC-MS (ESI) m/z: 440 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1.[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.C(OCC)C>[Cl:12][CH2:11][C:4]1[CH:3]=[C:2]([F:13])[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=1
Reactant: [F-]
Reactant: CC(C)c1nc(Cl)cc(CCl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)c1nc(F)cc(CCl)n1

Procedure:
A mixture of 0.8 g (0.0039 mol) of 6-chloro-4-chloromethyl-2-isopropyl-pyrimidine (see Example 61), 0.51 g (0.0089 mol) of anhydrous potassium fluoride and 0.14 g (0.0004 mol) of 18-crown-6 in 7 ml of acetonitrile is heated at reflux temperature for 48 hours. The mixture is then taken up in diethyl ether and the solution is washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and freed from solvent under reduced pressure. The 4-chloromethyl-6-fluoro-2-isopropyl-pyrimidine is obtained in the form of a yellow oil, 1H-NMR (CDCl3): 1.32 (d, CH(CH3)2), 3.18 (m, CH(CH3)2), 4.62 (s, CH2Cl), 6.99 (d, CH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:69][O:70][C:71](=[O:80])[C@H:72]([CH2:74][CH2:75][C:76]([O:78][CH3:79])=[O:77])[NH2:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:73][CH:72]([CH2:74][CH2:75][C:76]([O:78][CH3:79])=[O:77])[C:71]([O:70][CH3:69])=[O:80])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: COC(=O)CC[C@H](N)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol), HATU (110 mg, 0.29 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of L-glutamic acid dimethyl ester hydrochloride (66 mg, 0.31 mmol). The mixture was heated at 50° C. for 15 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give dimethyl 2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate as white solid. Yield: 130 mg, 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:15]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:15])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloropyridin-2-carboxylic acid (309 g, 1.96 mol) in anhydrous MeOH (2 L) was slowly added thionyl chloride (299.7 mL, 4.12 mol, 2.1 eq) at room temperature (cloudy solution became clear brown solution during the addition of thionyl chloride). After the addition was complete, the reaction mixture was heated to 50° C. and stirred at this temperature overnight. The solvent and excess thionyl chloride were removed under reduced pressure and the crude product was azeotroped with toluene twice. The resulting solid was transferred to a filter funnel and washed with saturated aqueous NaHCO3 until the filtrate was basic. The resulting solid was dissolved in dichloromethane (2 L) and washed with saturated aqueous NaHCO3. The organics were dried over sodium sulfate, filtered and the filtrate was concentrated to provide the title compound as an off-white solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7]Br)[CH3:5]>CN(C=O)C>[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][C:1]#[N:2])[CH3:5]
Reactant: [C-]#N
Reactant: CCCCC(CC)CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)CC#N
Reaction time: 2 h

Procedure:
A solution of KCN (3.8 g, 58 mmol) was stirred in DMF (150 mL) at room temperature. After the mixture was stirred for 2 h, a solution of 2-ethylhexylbromide (10 g, 52 mmol) in DMF (250 mL) was added dropwise at the same temperature. After stirring for 12 h at room temperature, the reaction mixture was concentrated by evaporation in vacuo. The crude product was diluted with water (100 mL) and diethyl ether (100 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were subsequently washed with NaOH-solution (2.5 M), saturated bicarbonate solution and brine, dried over MgSO4 and concentrated by evaporation in vacuo. The resulting brown oil was purified by vacuum distillation (45° C., 10−2 mbar) to afford a clearly yellow oil (VI). (3.2 g, 44%). 1H-NMR (CDCl3): δ=2.82-2.69 (m, 2H), 2.22-2.15 (m, 1H), 1.55-1.00 (m, 11H), 0.83-0.68 (m, 3H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[O:10])[CH:7]=1.[F:20][C:21]([F:33])([F:32])[C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26](Cl)=[O:27])=[O:23]>N1C=CC=CC=1>[CH3:19][O:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:24]2[C:22](=[O:23])[C:21]([F:33])([F:20])[F:32])=[O:27])=[CH:7][C:6]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)=[O:10]
Reactant: COc1ccc(N)cc1NC(=O)Nc1cnccn1
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)C(F)(F)F
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)[C@@H]2CCCN2C(=O)C(F)(F)F)cc1NC(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
A solution of 1-(5-amino-methoxyphenyl)-3-pyrazin-2-yl-urea (Compound 14, Example 4) (105 mg, 0.4 mmol) in dry pyridine (2 mL) at 0° C. was treated with a solution of N-trifluoroacetyl-(S)-prolyl chloride (0.1 M in dichloromethane, 4.5 mL, 0.45 mmol) and stirred 2 h at room temperature. The reaction was quenched with 1 N HCl (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with 1 N HCl (2×20 mL), water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to a beige solid (60 mg). Recrystallization from acetonitrile yielded the final solid product (30 mg, 17%). 1H NMR (300 Mhz, d6-DMSO) δ: (10.16-10.06, m, 3H), 8.90 (s, 1H), 8.36-8.30 (m, 2H), 8.25 (d, J=2.6 Hz, 1H), 7.42 (dd, J=8.8, 2.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 4.57 (dd, J=8.5, 4.4 Hz, 1H), 3.88 (s, 3H), 3.73 (t, J=6.5 Hz, 1H), 2.27-2.21 (m, 1H), 2.06-1.90 (m, 3H). LRMS (ESI, positive) m/e 453.1 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:7]([O:6][C:4]([C:3]1([C:1]#[N:2])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)CC#N
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C#N)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl cyanoacetate (2.50 g, 22 mmol) and 1,4-dibromobutane (5.00 g, 23.0 mmol) were dissolved in anhydrous DMF (20 ml) under nitrogen and cesium carbonate (21.0 g, 64 mmoles) added with water bath cooling. After stirring at room temperature for 18 h the reaction was diluted with water and extracted with ethyl acetate (2×80 ml), the organic layers were combined and washed with water (40 ml) and saturated aqueous sodium chloride solution (25 ml). The organics were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give 1-cyano-cyclopentanecarboxylic acid ethyl ester as an almost colourless oil (3.64 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([OH:15])=O.[N:16]1([CH:22]2[CH2:25][N:24]([C:26](=[O:29])[CH:27]=[CH2:28])[CH2:23]2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([N:19]1[CH2:20][CH2:21][N:16]([CH:22]2[CH2:25][N:24]([C:26](=[O:29])[CH:27]=[CH2:28])[CH2:23]2)[CH2:17][CH2:18]1)=[O:15]
Reactant: C=CC(=O)N1CC(N2CCNCC2)C1
Reactant: O=C(O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC(N2CCN(C(=O)Cc3c[nH]c4cc(Cl)c(Cl)cc34)CC2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
A mixture of 2-(5,6-dichloro-1H-indol-3-yl)acetic acid (90 mg, 0.372 mmol), 1-(3-(piperazin-1-yl)azetidin-1-yl)prop-2-en-1-one (87 mg, 0.446 mmol), EDCI.HCl (107 mg, 0.558 mmol), HOBt (75 mg, 0.558 mmol) in DMF (3 mL) at 0° C., Et3N (112 mg, 1.11 mmol) was added. The resulting mixture was stirred at RT for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=30:1) to afford the desired product (12 mg, 7.66% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ:11.19 (bs, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 7.35 (d, 1H), 6.28 (dd, J=9.6, 16.8 Hz, 1H), 6.09 (dd, J=2.4, 17.2 Hz, 1H), 5.66 (dd, J=2.4, 10.4 Hz, 1H), 4.21-4.18 (m, 1H), 4.02-3.98 (m, 1H), 3.93-3.88 (m, 1H), 3.78 (s, 2H), 3.74-3.70 (m, 1H), 3.53-3.47 (m, 4H), 3.10-3.07 (m, 1H), 2.25-2.19 (m, 4H). ESI-MS m/z: 423.3[M+1].
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[N:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N:38]5[CH2:39][CH2:40][N:35]([C:30]6[N:31]=[CH:32][CH:33]=[CH:34][N:29]=6)[CH2:36][CH2:37]5)=[CH:8][CH:7]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(c5ncccn5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In THF (7 ml) was dissolved N-[4-(chloromethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 1-(2-pyrimidyl) piperazine (190 mg). The mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-[4-[1-(2-pyrimidyl)-4-piperazinylmethyl]-phenyl]-3,4-dihydronaphthalene-2-carboxamide (Compound 42) (166 mg) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[O:12]1[C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:21])[C:15]=2[CH:14]=[CH:13]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:11][C:4]1[CH:3]=[C:2]([N:17]2[CH:18]=[CH:19][C:20]3[O:12][CH:13]=[CH:14][C:15]=3[C:16]2=[O:21])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=c1[nH]ccc2occc12
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccc3occc3c2=O)ccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 15 h
Yield: 108.6 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (2.3 mL, 19 mmol) was added to a suspension of furo[3,2-c]pyridin-4(5H)-one (2.115 g, 15.67 mmol) and Cs2CO3 (5.097 g, 15.67 mmol) in anhydrous DMF (100 mL) and the resulting suspension was heated to 125° C. and stirred for 15 h. H2O was added and the aqueous suspension was filtered. The solid was dried under reduced pressure to afford 4.6 g of crude 5-(3-methyl-4-nitrophenyl)furo[3,2-c]pyridin-4(5H)-one, which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[N+:17](=[CH:19][CH3:20])=[N-:18]>CCOCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](=[O:13])[C:19](=[N+:17]=[N-:18])[CH3:20])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccn2)cc1
Reactant: CC=[N+]=[N-]
Solvent: CCOCC
Product: CC(=[N+]=[N-])C(=O)c1ccc(Oc2ccccn2)cc1

Procedure:
To a solution of 4-(2-pyridyloxy)benzoyl chloride in ether, a solution of diazoethane in ether is added dropwise, and the reaction is effected as in Example 8 (2) to give 4-(2-pyridyloxy)-1-(2-diazopropionyl)benzene (4.72 g). This substance is recrystallized from ethyl acetate to give crystals melting at 101° to 102° C (decomp.). IR (CCl4): 2070, 1630, 1590 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:11](=[O:12])[C@H:10]2[CH2:13][CH2:14][CH2:15][C@H:9]2[NH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[Br:24][CH2:25][C:26](Br)=[O:27]>C(OCC)(=O)C.CCCCCC>[Br:24][CH2:25][C:26]([N:8]1[C@@H:9]2[CH2:15][CH2:14][CH2:13][C@@H:10]2[C:11](=[O:12])[N:5]([CH2:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[F:1])[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]1=2)=[O:27]
Reactant: O=C(Br)CBr
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccccc1F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1Cc1ccccc1F
Yield: 62 %

Procedure:
Using (3aR*,10aS*)-9-(2-fluorobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized in substantially the same manner as in Working Example 122 in a yield of 62%, m.p. 198.5°-199.6° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][C:2]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COC(=O)c1cccc(O)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Product: COC(=O)c1cccc(O)c1NC(=O)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
A solution of 1.0 g (4.9 mmol) of methyl 2-amino-3-hydroxybenzoate 9bb, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9 cc, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9dd, which was used without purification. MS m/z (M+H+) 290.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Clc1ncccn1
Product: C[C@@H](c1ccc(-c2ncccn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-chloropyrimidine in Step 4. LC-MS Method 2 tR=1.401, m/z=436.1; 1H NMR (CDCl3) 1.53 (d, 3H), 1.62 (m, 1H), 1.81-1.98 (m, 3H), 2.15 (m, 2H), 2.31 (m, 1H), 2.76 (m, 1H), 3.51 (t, 2H), 5.67 (m, 1H), 6.92 (m, 4H), 7.11 (m, 1H), 7.19 (m, 1H), 8.15 (d, 2H), 8.71 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH2:36][CH3:37])[CH:7]([CH3:8])[CH:6]([O:9][C:10](=[O:32])[CH:11]([CH2:28][CH2:29][CH2:30][CH3:31])[C:12]([O:14][CH:15]2[CH2:20][C:19]([CH3:23])([CH2:21][CH3:22])[NH:18][C:17]([CH3:26])([CH2:24][CH3:25])[CH:16]2[CH3:27])=[O:13])[CH2:5][C:4]([CH3:35])([CH2:33][CH3:34])[NH:3]1.[C:38]([C:42]1[CH:43]=[C:44]([CH:49]=[C:50]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:51]=1[OH:52])[CH2:45]N(C)C)([CH3:41])([CH3:40])[CH3:39].[NH2-].[Li+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:26][C:17]1([CH2:24][CH3:25])[CH:16]([CH3:27])[CH:15]([O:14][C:12](=[O:13])[C:11]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:45][C:44]2[CH:49]=[C:50]([C:53]([CH3:54])([CH3:56])[CH3:55])[C:51]([OH:52])=[C:42]([C:38]([CH3:40])([CH3:39])[CH3:41])[CH:43]=2)[C:10]([O:9][CH:6]2[CH2:5][C:4]([CH3:35])([CH2:33][CH3:34])[NH:3][C:2]([CH3:1])([CH2:36][CH3:37])[CH:7]2[CH3:8])=[O:32])[CH2:20][C:19]([CH3:23])([CH2:21][CH3:22])[NH:18]1
Reactant: CCCCC(C(=O)OC1CC(C)(CC)NC(C)(CC)C1C)C(=O)OC1CC(C)(CC)NC(C)(CC)C1C
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCC(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)(C(=O)OC1CC(C)(CC)NC(C)(CC)C1C)C(=O)OC1CC(C)(CC)NC(C)(CC)C1C

Procedure:
26.2 g (0.05 mole) of butylmalonic acid-bis(2,3,6-trimethyl-2,6-diethyl-4-piperidinyl)ester and 13.2 g (0.05 mole) of N-(3,5-di-tert.butyl-4-hydroxybenzyl) dimethylamine are dissolved in 200 ml of toluene. After the addition of 0.25 g of lithium amide, the mixture is refluxed for 4 hours. After cooling, the mixture is neutralised with 1.5 ml of 1% acetic acid, and the organic phase is repeatedly washed with water. After drying over Na2SO4, the solution is concentrated in vacuo. As residue there is obtained butyl-(3,5-di-tert.butyl-4-hydroxybenzyl)malonic acid-bis(2,3,6-trimethyl-2,6-diethyl-4-piperidinyl) ester in the form of viscous oil (Compound No. 32).