Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:19])=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To 5.4 g of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid in 50 mL of methanol and 100 mL of chloroform was at 0° C. was added 15 mL of 2 M (trimethylsilyl)diazomethane in hexanes. After allowing the reaction to warm to ambient temperature and stirring for 2 hours, the solvents were removed and the crude product purified by passing through a plug of silica gel with chloroform. The product was then recrystallized from hexanes to give 5.8 g (100%) of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid, methyl ester: mp=90-96° C. (decomposed); mass spectrum (m/e): M+H 287.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][C:13](C)([O-])C.[Li+].C([Mg]Br)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)[O-]
Agent: CC[Mg]Br
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc(Cl)ncc1[N+](=O)[O-]

Procedure:
In Scheme A, reaction of 2,4-dichloro-5-nitropyrimidine (1) with lithium t-butoxide, cuprous iodide and ethylmagnesium bromide in THF at -78° C. gives 2-chloro-4-ethyl-5-nitropyrimidine (2). Displacement of the 2-chloro group in 2, is accomplished by treatment with 2-ethyl-4-methylimidazole or imidazole in acetonitrile at room temperature. Reduction of the nitro moiety in 3 to produce 4 is accomplished as illustrated. Reduction of 2,6-dichloro-4-ethyl-5-nitropyrimidine (5) is accomplished as illustrated to produce the compound 4 where R is hydrogen. ##STR6##
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[C:19]([C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])[CH:18]=[C:17]([CH2:33]Br)[N:16]=1)=[O:14])[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17]([CH2:33][N:1]2[CH2:9][CH2:8][N:7]([CH2:33][C:17]3[CH:18]=[C:19]([C:21]4[C:22]([O:31][CH3:32])=[CH:23][C:24]([O:29][CH3:30])=[CH:25][C:26]=4[O:27][CH3:28])[CH:20]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[N:16]=3)[CH2:6][CH2:5][N:4]([CH2:33][C:17]3[N:16]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH:20]=[C:19]([C:21]4[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=4[O:31][CH3:32])[CH:18]=3)[CH2:3][CH2:2]2)[CH:18]=[C:19]([C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])[CH:20]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(CBr)n1
Reactant: C1CNCCNCCN1
Solvent: CC#N
Product: CCOC(=O)c1cc(-c2c(OC)cc(OC)cc2OC)cc(CN2CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CCN(Cc3cc(-c4c(OC)cc(OC)cc4OC)cc(C(=O)OCC)n3)CC2)n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
1,4,7-triazacyclononane (31.5 mg) and compound 14 (0.3 g, 0.76 mmol) were dissolved in dry acetonitrile (20 mL) Potassium carbonate (0.17 g) was added and the mixture was refluxed overnight. The mixture was allowed to cool to room temperature, filtered and concentrated. Purification on silica gel (eluent CH2Cl2:EtOH:HOAc; 80:20:1, v/v/v) yielded the title compound (0.17 g, 62%). ESI-MS: [M+H]+ 1117.5 calc. for C60H73N6O15+ 1117.5
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([NH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:27]3[CH:28]=[C:23]([NH:22][S:19]([CH3:18])(=[O:20])=[O:21])[CH:24]=[CH:25][CH:26]=3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CS(=O)(=O)Nc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with 3-(methylsulfonylamino)phenylboronic acid via General Procedure A to give crude 3-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)-N-methylsulfonylbenzenamine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 121 after purification by reverse HPLC. MS (Q1) 485 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH:7]([CH2:10]O)[CH2:8][O:9][C:4]=2[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:33]([O:37][C:38]([NH:40][S:41]([NH2:44])(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCCC>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[S:41]([NH2:44])(=[O:43])=[O:42])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)NS(N)(=O)=O
Reactant: OCC1COc2cc(Cl)ccc2O1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C[C@H]1COc2cc(Cl)ccc2O1)S(N)(=O)=O

Procedure:
To (6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol (9.5 mg, 0.042 mmol), PPh3 (17 mg, 0.066 mmol) and N-(t-butoxycarbonyl)sulfamide (16 mg, 0.083 mmol) in Ethyl acetate (0.5 mL) was added diisopropyl azodicarboxylate (DIAD, 0.013 mL, 0.066 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h (monitored with TLC 40% ethyl acetate-heptane and LC-MS) and then concentrated to a residue. The residue loaded onto a 12 g ISCO silica column in CH2Cl2 and eluted with 0-30% ethyl acetate/heptane to yield the title compound as a gum, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccc(F)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-fluoro-aniline (43 mg, 0.39 mmol). The title compound was obtained as a solid (60 mg, 41% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.58 (1H, s), 9.00 (2H, s), 8.69 (1H, s), 7.67 (2H, m), 7.21 (2H, m). MS m/z: 442.06, 444.06 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11](/[CH:13]=[N:14]/[S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:21]C(C)=O.C(=O)=O.C[Mg+].[Br-].CCOC(C)=O.CO>C(Cl)Cl.C(OCC)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C@@H:13]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:21])[N:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC(C)(C)[S@](=O)/N=C/c1cn(-c2ccc(Cl)cc2)cn1
Agent: C[Mg+]
Agent: O=C=O
Agent: [Br-]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: C[C@H](N[S@@](=O)C(C)(C)C)c1cn(-c2ccc(Cl)cc2)cn1
Temperature: -40 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of (S,E)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.69 g, 5.45 mmol) in DCM (27 mL), cooled to −40° C. (acetone/dry ice) under N2, was added 3M MeMgBr (7.27 ml, 21.8 mmol) in diethyl ether. Reaction mixture allowed to stir for 1 hr at −40° C. Reaction mixture was quenched with the slow addition of a saturated solution of NH4Cl and diluted with EtOAc. Phases partitioned, aqueous phase extracted with EtOAc and the organic layers combined washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/MeOH:EtOAc 0 to 5%) provided (S)—N—((S)-1-(1-(4-chlorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (1.11 g, 3.41 mmol, 62% yield). 1H NMR (400 MHz, CDCL3) δ 1.25 (s, 9H) 1.58 (d, J=6.65 Hz, 3H) 3.80 (d, J=5.48 Hz, 1H) 4.59 (quin, J=6.36 Hz, 1H) 7.26 (s, 1H) 7.33 (d, J=8.61 Hz, 2H) 7.41-7.47 (m, 2H) 7.76 (d, J=1.17 Hz, 1H). LCMS m/z 326.1 (M+H)+, Rt 0.59 min.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][F:16])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[ClH:1].[F:16][CH2:15][CH:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1
Reactant: FCC1CN(Cc2ccccc2)CCO1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: FCC1CNCCO1
Yield: 64.9 %

Procedure:
To a solution of N-benzyl-2-fluoromethylmorpholine hydrochloride (1.46 g) in ethanol (85 ml) is added 10% palladium-carbon (0.2 g), and the mixture is stirred under hydrogen atmosphere (maximum hydrogen pressure: 6 kg/cm2) at room temperature. After completion of absorption of hydrogen gas, palladium-carbon is filtered off, and the filtrate is concentrated under reduced pressure. To the residue are added ether (2 ml) and ethanol (0.5 ml), and the precipitated crystals are separated by filtration and dried under reduced pressure to give the title compound (0.6 g).
Reaction SMILES: [CH2:1]([O:19][C:20](=[O:43])[CH:21]([NH:32]C(OCC1C=CC=CC=1)=O)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([O:19][C:20](=[O:43])[CH:21]([NH2:32])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(N)Cc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
2-Benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid Stearyl Ester (430 g) was dissolved in ethyl acetate (2500 ml) in a pressure vessel. 10% Palladium carbon (58 g, 50% wet) was added and the reaction mixture was stirred under an atmosphere of Hydrogen (10 Kg) at 50° C. for 12 hours. The reaction mixture was brought to 20° C. and the catalyst was removed by filtration. The solvent was distilled off and the resulting diamine was precipitated by adding hexane. It was filtered and dried to yield pure 2-amino-3-(4-amino-phenyl)-propionic acid octadecyl ester (200 g) as a white powder with a melting point of 54-56° C. and a purity of 98% as determined by HPLC. The product was further characterized by IH NMR (CDCl3) δ 0.90 (t, 3H, CH3), 1.25 (m, 30H, 15×CH2), 1.65 (m, 2H, CH2), 2.90-3.05 (m, 2H, CH2), 3.70 (m, 1H, CH), 4.00-4.15 (m, 6H, 2×NH2 & CH2), 6.60 (d, 2H, Ar), 6.95 (d, 2H, Ar)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[CH:5]=[N:6][CH:7]=1.[C:12](Cl)(=O)[CH3:13]>N1C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[N:9]=[C:12]([CH3:13])[O:11][N:10]=2)[CH:3]=1
Reactant: NC(=NO)c1cncc(Br)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1nc(-c2cncc(Br)c2)no1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-N′-hydroxypyridine-3-carboximidamide (1.0 eq.) in pyridine was added acetyl chloride (2 eq). The reaction stirred at 100° C. for 1 h and 2 eq of acetyl chloride was added. After 1 h, the mixture was cooled, diluted with EtOAc and aqueous NaHCO3. The organic extracts were washed with aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 70:30) afforded the title compound as a white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1[C:36]2[C:31](=[CH:32][C:33]([C:37](O)=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[N:27]=[CH:28][CH:29]=[CH:30]4)=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc2ncccc2c1

Procedure:
The title compound, yellow solid (106 mg, 88%), MS (ISP) m/z=482.4 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and quinoline-6-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:34]=CC)=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:37]1CCCC1>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:34]=[O:37])=[C:20]([NH:23][C:24]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC=Cc1c(NC(=O)OCc2ccccc2)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(NC(=O)OCc4ccccc4)c(C=O)c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution {(2R)-7-{[(benzyloxy)carbonyl]amino}-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (4.5 g, 8.84 mmole) in tetrahydrofuran (225 mL) was added OSO4 (1.65 mL, 0.270 mmole). Then a solution of NaIO4 (9.45 g, 44.2 mmole) in water (100 mL) was added dropwise. The reaction was stirred at room temperature under nitrogen overnight. Water (250 mL) was added to the mixture and it was then extracted with ethyl acetate. The organic phase was then washed with brine, dried over magnesium sulfate, filtered and evaporated to 4.45 g (>95%) of the (R)-enantiomer of the title compound as a yellow solid. 1H (CDCl3) broad singlet 10.8 δ (1H); singlet 10.1 δ (1H); doublet 7.9 δ (1H); doublet 7.8 δ (2H); multiplet 7.4 δ (7H); doublet 7.0 δ (1H); singlet 5.2 δ (2H); multiplet 4.5 δ (1H); multiplet 4.2 δ (3H); multiplet 4.1 δ (1H); singlet 2.4 δ (3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5](=[O:18])[CH2:6][CH:7]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH2:9].C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:19])[C:4](=[N+:29]=[N-:30])[C:5](=[O:18])[CH2:6][CH:7]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:8]=[CH2:9]
Reactant: C=CC(CC(=O)CC(=O)OC)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Product: C=CC(CC(=O)C(=[N+]=[N-])C(=O)OC)OCc1ccccc1
Yield: 98.6 %

Procedure:
In accordance with the process of Example 2, 5-benzyloxy-3-oxo-6-heptenoic acid methyl ester (1.07 g; 4.1 m mol), p-toluenesulfonyl azide (810 mg; 4.1 m mol) and triethylamine (450 mg; 4.5 m mol) were used as starting materials to obtain 1.16 g of 5-benzyloxy-2-diazo-3-oxo-6-heptenoic acid methyl ester as yellow oily product.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:16]=[CH:17][C:12]=2[C:11](=[O:24])[C:10]([C:25]([O:27]CC)=[O:26])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:16]=[CH:17][C:12]=2[C:11](=[O:24])[C:10]([C:25]([OH:27])=[O:26])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)c2nc(N3CCNCC3)ncc2c1=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cn(Cc2ccccc2)c2nc(N3CCNCC3)ncc2c1=O
Temperature: 90 °C
Yield: 79 %

Procedure:
Ethyl 8-benzyl-5,8-dihydro-2-(1-piperazinyl)5-oxopyrido[2,3-d]pyrimidine-6-carboxylate (1.5 g) was dissolved in 20 ml of a 12% aqueous solution of sulfuric acid by heating at 90°C for one hour. The resulting solution was filtered to remove a small amount of the insoluble material and the filtrate was neutralized with 28% aqueous ammonia, to separate a solid which was collected, washed with water, and recrystallized from dimethylformamide. There is obtained 1.1 g of the product, m.p. 250° -253°C.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16]([N:18]4[CH2:23][CH2:22][CH:21]([C:24](OCC)=O)[CH2:20][CH2:19]4)=O)[CH2:15][CH:6]([C:7]4[C:12]3=CC=CC=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-:35].[Na+].O>O1CCCC1>[CH:5]1[C:14]2[C:13]3([CH2:16][N:18]4[CH2:23][CH2:22][CH:21]([CH:24]([C:20]5[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=5)[OH:35])[CH2:20][CH2:19]4)[CH2:12][CH:7]([C:6]4[C:15]3=[CH:3][CH:2]=[CH:1][CH:14]=4)[C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: [OH-]
Reactant: CCOC(=O)C1CCN(C(=O)C23CC(c4ccccc42)c2ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1cccnc1)C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of ethyl 1-(9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)-4-piperidine carboxylate (33.0g, 88.4 mmol) in tetrahydrofuran (50 mL) was added dropwise to a suspension of lithium aluminum hydride (4.70 g, 123.8 mmol) in tetrahydrofuran (70 mL) held at reflux temperature. Upon complete addition, the mixture was held at reflux for 2 h, then was cooled to 0° C. and treated sequentially with 10% aqueous sodium hydroxide (4.7 mL), water (4.7 mL) and 10% aqueous sodium hydroxide (14.1 mL). The resulting white slurry was stirred for 30 minutes, treated with diatomaceous earth (25 g) and filtered through a pad of diatomaceous earth. The filter cake was washed with tetrahydrofuran/methanol (20:1, 2×200 mL). The filtrate was evaporated to give the title compound as a tan solid (23.5 g, 77.0 mmol, 87%) 1H NMR (d6-DMSO): δ7.25 (m, 2H), 7.18 (m, 2H), 4.38 (t, J=5.2 Hz, 1H, CH2OH), 4.29 (s, 1H, H--C(10)), 3.32 (s, 2H, CH2N), 3.21 (m, 2H, CH2OH), 2.97 (d, J=11.2 Hz, 2H, eq-H--C(2')), 2.44 (s, 2H, H--C(11)), 2.14 (dd, J=11.2, 11.2 Hz, ax-H--C(2')), 1.58 (d, J=11.0 Hz, eq-H--C(3')), 1.34 (m, 1H, H--C(4')), 1.10 (ddd, J=3.5, 11.0, 11.2 Hz, 2H, ax-H--C(3')).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([N:9]1[C:10](=[O:12])[CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13])=[O:18]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1ccccc1Cl
Yield: 13 %

Procedure:
In a similar manner to Example 8, 560 mg (3.18 mmol) of 1-phenyl-imidazolidin-2,4-dione were reacted with 560 mg (3.22 mmol) of 2-chlorobenzoyl chloride. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The resultant residue was purified by column chromatography on silica gel (developing solvent: methylene chloride) and subjected to crystallization from n-hexane/ethyl acetate to obtain 130 mg (yield: 12.9%) of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([Br:32])=[CH:26][C:23]=1[CH:24]=[O:25]>>[Br:32][C:27]1[C:28]([O:30][CH3:31])=[CH:29][C:22]([O:21][CH3:20])=[C:23]([CH:24]([OH:25])[C:9]#[C:8][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:26]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1cc(OC)c(C=O)cc1Br
Product: COc1cc(OC)c(C(O)C#Cc2ccccc2)cc1Br
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,4-dimethoxy-5-bromobenzaldehyde was reacted to give the title compound as a yellow foam (1.43 g, 100%). LCMS (Method B): RT=4.99 min, [M+Na]+=369/371.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[N:13]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Reactant: ICCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n(CCN3CCOCC3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
500 mg (0.980 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.270 mmol) of cesium carbonate and 259 mg (1.08 mmol) of 4-(2-iodoethyl)morpholine were added and the mixture was stirred at RT for 18 h, at 40° C. for 18 h and at 100° C. for 8 h. After cooling, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The purification was effected by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 102 mg (17% of theory) of the title compound were obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(NC(C)C)(C)C>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.[Cu]I.C1COCC1>[N:10]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:3][CH:4]=2)=[O:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(c1ccc(I)cc1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 57 °C
Yield: 99.8 %

Procedure:
To a mixture under Ar of (4-iodo-phenyl)-morpholin-4-yl-methanone (273 mg), trimethylsilylacetylene (169 mg), [PdCl2(PPh3)2] (30 mg) and copper(i) iodide (15 mg) is added a degassed mixture of THF (4.5 ml) and diisopropylamine (4.5 ml). After stirring over night at 57° C. and aqueous work up, the organic layer is dried over Na2SO4 and the solvent is evaporated. Flash chromatography (silica gel, CH2Cl2/MeOH/25% NH4OH 97:3:0.3) yields 247 mg of morpholin-4-yl-(4-trimethylsilanylethynyl-phenyl)-methanone as a light brown solid, 1H-NMR (300 MHz): 0.26 (s, 3H); 3.32-3.91 (br, 8H); 7.34 (d, J=6.5, 2H); 7.51 (d, J=6.5, 2H).