Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6](S(C2C=NC=CC=2)(=O)=O)[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[C:2]1[NH:6][CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:3]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: [Na+]
Product: CN(Cc1c[nH]c(-c2cc(F)ccc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 301 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,5-difluorophenyl)boronic acid (220 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 135 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19]>>[C:18]([OH:21])(=[O:20])[CH3:19].[C:18]([OH:21])(=[O:20])[CH3:19].[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CC(=O)O
Temperature: 135 °C
Reaction time: 4 h

Procedure:
Into a reactor was charged 880g of bisphenol-A and 1000g of acetic anhydride. The reaction was heated to about 135° C. and held at this temperature for about 4 hours. The reaction was vacuum distilled for partial removal of acetic anhydride. Analysis of the crude product showed that conversion to bisphenol-A diacetate was 99.9% complete. The material also contained some residual acetic anhydride (less than 600 ppm based on weight of bisphenol-A diacetate as measured by titration with morpholine as described in Siggia and Hana, "Quantitative Organic Analysis via Functional Groups", Fourth Edition, Wiley-Interscience, 1979, pages 231 to 235).
Reaction SMILES: C(C1C=[C:5](C=CC=1OC)[C:6](OC)=[O:7])#N.[OH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26]>>[C:6]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[C:25]([F:26])([F:27])[F:28])(=[O:7])[CH3:5]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Reactant: O=C(O)c1ccc(O)c(C(F)(F)F)c1
Product: CC(=O)Oc1ccc(C(=O)O)cc1C(F)(F)F

Procedure:
A reaction and treatment was carried out in the same manner as in Reference Example 62 except that the methyl 3-cyano-4-methoxybenzoate used in Reference Example 62 was replaced with methyl 4-methoxy-3-trifluoromethyl benzoate, thereby giving 4-hydroxy-3-trifluoromethylbenzoic acid. Using this compound, a reaction and treatment was carried out in the same manner as in Reference Example 80, thereby giving the desired compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([OH:11])=O)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.Br.[Br:49][CH2:50][CH2:51][CH2:52][NH2:53]>CN(C=O)C>[C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([NH:53][CH2:52][CH2:51][CH2:50][Br:49])=[O:11])(=[O:3])[CH3:2]
Reactant: NCCCBr
Reactant: CC(=O)c1cccc(OCC(=O)O)c1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(OCC(=O)NCCCBr)c1
Reaction time: 0.67 h

Procedure:
A solution of (3-acetyl-phenoxy)-acetic acid (0.194 g, 1.0 mmol) and diisopropylethylamine (0.38 g, 3 mmol) in dry DMF (3 ml) is treated with [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (0.38 g, 1.0 mmol). After stirring for 5 minutes 3-bromo-propylamine hydrobromide (0.26 g, 1.2 mmol) is added and stirring continued for a further 40 minutes. The solvent is evaporated and the crude mixture partitioned between ethylacetate and saturated aqueous NaHCO3. The ethyl acetate phase is dried over MgSO4 and evaporated to afford 2-(3-acetyl-phenoxy)-N-(3-bromopropyl)-acetamide. This crude material is taken up in acetonitrile (3 ml) and treated with triethylamine (0.38 g, 3 mmol) and 3-(4-fluoro-phenoxy)-azetidine hydrochloride (0.11 g, 1.2 mmol). The reaction mixture is stirred at ambient temperature for 20 hours, the solvent evaporated and the crude product purified by flash silica chromatography (elution 10:90 methanol/dichloromethane) to afford 2-(3-acetyl-phenoxy)-N-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-acetamide. [MH]+ 401.14.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[C:12]([Br:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(C)(C)C>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:13]=3[C:12]([Br:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Reactant: C1CCNCC1
Solvent: CC(C)(C)O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(N3CCCCC3)ncnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 2.0 g (5.37 mmol) of the product from Method U and 1.1 g (13.4 mmol) of piperidine in 10 mL of tert-butanol was heated with stirring at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (25 mL) and water (25 mL). The dichloromethane layer was dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 2.2 g (97%) of the title compound. 1H NMR (400 MHz) (CDCl3) δ: 1.63-1.72 (m, 6H), 3.54-3.57 (m, 4H), 7.53 (t, 2H, J=2.0 Hz), 7.60 (s, 1H), 7.61 (t, 1H, J=2.0 Hz), 8.17-8.20 (m, 2H), 8.43 (s, 1H). LRMS: 422.7, 420.7 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.C(Cl)(Cl)=O.[Cl:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH:14]=[CH:15][CH:16]=1.CN>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:18](=[O:27])[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:3][N:2]([CH3:5])[CH:1]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: O=C(Cc1cccc(Cl)c1)Cc1cccc(Cl)c1
Agent: CN
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1cc(-c2cccc(Cl)c2)c(=O)c(-c2cccc(Cl)c2)c1
Reaction time: 3 h

Procedure:
The aminoformylating reagent was made by adding 30 g. of dimethylformamide dropwise to 20 g. of phosgene in 150 ml. of chloroform at 0° C. A 10 g. portion of 1,3-bis(3-chlorophenyl)-2-propanone in 50 ml. of chloroform was then added. The mixture was stirred for 3 hours, after which 50 ml. of 40% aqueous methylamine was added. Chloroform was then evaporated from the mixture, and 200 ml. of ethanol and 50 ml. of additional 40% aqueous methylamine were added. The mixture was then stirred under reflux overnight. In the morning, the product was extracted as described in the example above, and chromatographed on a silica gel column with ethyl acetate containing successively larger quantities of methanol. The product, 3,5-bis(3-chlorophenyl)-1-methyl-4(1H)-pyridone, 0.85 g., melted at 164°-167° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:6]2[CH:7]=[N+:8]([O-:26])[CH:9]=[CH:10][C:5]=2[N:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH:3]=1
Reactant: O=C(OCc1ccccc1)n1cc(Cl)c2cnccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1cc(Cl)c2c[n+]([O-])ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
A stirred suspension of benzyl 3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.4 g, 8.37 mmol) in dichloromethane (20 mL) was treated portion wise with 3-chloroperoxybenzoic acid (2.165 g, 12.55 mmol) followed by stirring at room temperature for about 1.5 hours. The reaction was neutralized with saturated aq. sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to afford benzyl 3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate 5-oxide (2.45 g, 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[C:16]([C:18]1[N:19]=[C:20]([C:31](O)=[O:32])[N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=1)#[N:17].[K]>>[CH3:1][C:2]1([CH3:15])[CH2:3][CH2:4][N:5]([C:8]2[C:13]([NH:14][C:31]([C:20]3[N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:18]([C:16]#[N:17])[N:19]=3)=[O:32])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)CCN(c2ncccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: [K]
Product: CC1(C)CCN(c2ncccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
4,4-Dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine (as prepared in above step) was coupled with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 11, step (d), as described in Example 32, step (c) to afford 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-amide which was subjected to SEM deprotection as described in Example 47, step (d) to afford the title compound. 1H-NMR (DMSO-d6; 400 MHz): δ 14.4 (s, 1H), 9.72 (s, 1H), 8.39 (m, 2H), 8.11 (dd, 1H, J=4.8, 1.7 Hz), 7.13 (dd, 1H, J=4.8, 1.7 Hz), 3.02 (m, 4H), 1.56 (m, 4H), 1.01 (s, 6H); Mass spectrum (ESI, m/z): Calcd. for C17H20N6O, 325.1 (M+H), found 325.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10]Br.[NH:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[K]>CN(C)C=O>[C:23]([O:22][C:20]([N:12]([CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: COc1ccc(Br)c(CBr)c1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
A mixture of 4-bromo-3-bromomethylanisole (24 g, 86 mmol) and potassium di-tert-butyl iminodicarboxylate (24 g, 94 mmol) in dimethylformamide (200 mL) was stirred under argon at room temperature for 18 hr. The reaction was then concentrated under vacuum and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried(MgSO4), and concentrated. The residue was recrystallized from hexane to give the title compound (15 g, 42%) as a white solid: 1H NMR (CDCl3) δ 7.40 (d, J=8.6 Hz, 1 H), 6.68 (m, 2 H), 4.81(s, 2 H), 3.74 (s, 3 H) 1.44 (s, 18 H).
Reaction SMILES: FC(F)(F)S(O[C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])(=O)=O.[NH2:15][C:16](C)([CH3:19])[CH2:17]O.C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl>[CH3:12][C@H:7]1[C:8](=[O:9])[O:10][CH2:11][C:16]([CH3:19])([CH3:17])[NH:15]1
Reactant: CC(C)(N)CO
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(C)(C)COC1=O
Temperature: -40 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A solution of triflate 14 (5.00 g, 0.021 mol) in anhydrous CH2Cl2 (80 mL) under an N2 atmosphere, was cooled to −40° C. and was treated with a solution of 2-amino-2-methyl-1-propanol (2.5 folds, 4.68 g, 0.0525 mol) in anhydrous CH2Cl2 (10 mL). After stirring for 2 h at −40° C., the reaction mixture was warmed slowly to 0° C. then to room temperature and stirred overnight. The reaction mixture was treated with saturated aqueous NaHCO3 solution (100 mL). The organic phase was washed (water, brine), separated, and dried (Na2SO4). The aqueous layer was extracted with EtOAc (twice). The organic layer was separated, washed (water, brine) and dried (Na2SO4). The organic extracts were combined and concentrated to give a yellow oil. Column chromatography on silica gel using hexanes-EtOAc (1:2) to EtOAc gave 1.88 g (63%) of 15 as a light yellow oil: [α]23D −75° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 4.11 (s, 2H), 3.71 (q, 1H, J=6.8), 1.39 (d, 3H, J=6.8 Hz), 1.26 (s, 3H), 1.18 (s, 3H); 13C NMR (CDCl3) δ 229.2, 77.6, 49.5, 49.3, 27.2, 24.2, 18.4; LCMS (APCI) m/z 144.3 [(M+H)+, M=C7H13NO2]; Anal. (C7H13NO2) calcd: C, 58.72; H, 9.15; N, 9.78. found: C, 58.60; H, 9.35; N, 9.79. Note: 1H NMR data is similar with the data reported in the literature for the racemic compound (Koch, T. H.; Olesen, J. A.; DeNiro, J., J. Am. Chem. Soc. 1975, 97, (25), 7285-7288).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCCc2[nH]c3ccc(F)cc3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cc(F)ccc1n2Cc1ccccc1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
6-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.3938 g, 0.0019 mol) is added to a slurry of pentane-washed NaH (0.0970 g, 0.0024 mol) in DMF (3 mL) and after stirring for 10 min, benzyl bromide (0.28 mL, 0.0024 mol) is added. After stirring for 4 h at room temperature, the mixture is partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane/heptane (60/40 to 80/20 to 100/0) to give 0.3681 g (65%) of the title compound. An aliquot is recrystallized from ethyl acetate/heptane; MS (ESI+) for C19H16FNO m/z 294.2 (M+H)+; IR (drift) 1634, 1523, 1483, 1466, 1447, 1357, 1254, 1138, 900, 868, 803, 799, 759, 729, 700 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.88, 5.32, 6.95, 7.01, 7.15, 7.30, 7.96. Anal. Calcd for C19H16FNO: C, 77.80; H, 5.50; N, 4.78. Found: C, 77.65; H, 5.39; N, 4.69.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:46][CH3:47])=[C:21]([NH:24][C:25](=[O:45])[CH:26]=[CH:27][CH2:28][N:29]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:30][CH2:31]OS(C)(=O)=O)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.O>CN(C)C=O>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:46][CH3:47])=[C:21]([NH:24][C:25](=[O:45])[CH:26]=[CH:27][CH2:28][N:29]([CH2:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:30][CH2:31][S:3][C:1](=[O:4])[CH3:2])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCOS(C)(=O)=O)CC(=O)OC(C)(C)C
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCSC(C)=O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34 mg of potassium thioacetate are added to 150 mg of 4-[(3-bromophenyl)amino]-6-[(4-(N-[(tert-butyloxycarbonyl)methyl]-N-[2-(methylsulphonyloxy)ethyl]amino}-1-oxo-2-buten-1-yl)amino]-7-methoxy-quinazoline in 1 ml of dimethylformamide at ambient temperature. The reaction mixture is stirred overnight at ambient temperature and then combined with water for working up. The aqueous phase is separated off and extracted with ethyl acetate, the combined organic phases are dried over magnesium sulphate and freed from solvent in the rotary evaporator. Yield: 20 mg (14% of theory), Rf value: 0.62 (silica gel, ethyl acetate/methanol=15:1) Mass spectrum (EI): m/z=643, 645 [M]+
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18].Br[CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C:13]1=[O:18]
Reactant: CN1CCNCC1=O
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCN(C)C(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
DIPEA (0.52 ml, 2.96 mmol) and 1-methylpiperazin-2-one hydrochloride (0.22 g, 1.48 mmol) were sequentially added to a solution of ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) in acetonitrile (4 ml). The reaction was stirred at room temperature for 1.5 hours. DIPEA (0.13 ml, 0.74 mmol) was added again and the reaction was stirred at room temperature overnight. The solvent was evaporated and the crude was purified by flash chromatography (DCM/Acetone=9/1) to obtain ethyl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (256 mg, 75% yield) as a yellow oil.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([NH:19]N)=O>>[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[NH:19][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: N=C(N)c1ccccc1
Reactant: NNC(=O)c1sccc1Cl
Agent: Cl
Product: Clc1ccsc1-c1nc(-c2ccccc2)n[nH]1

Procedure:
The title compound was prepared from benzamidine hydrochloride and 3-chloro-thiophene-2-carboxylic acid hydrazide by a procedure similar to Example 88b as a yellowish solid (0.141 g, 37%). 1H NMR (DMSO-d6): 8.04 (d, J=9.6 Hz, 2H), 7.80 (d, J=6.0 Hz, 1H), 7.55 (d, J=7.80 Hz, 3H), 7.19 (d, J=5.70 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[OH-].[Na+].[C:13]1([CH2:19][CH2:20]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: BrCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
6.648 g of methylsulphonyl-acetic acid ethyl ester are added dropwise at -30°, within 30 minutes, to 1.745 g of sodium hydroxide dispersion (55% in oil) in 40 ml of DMF. The solution is subsequently stirred for 15 minutes, then heated and, within 150 minutes, under reflux, 7.4 g of 2-phenylethyl bromide in 10 ml of DMF are added dropwise thereto. The reaction mixture is then stirred for 20 minutes, acidified with 12 ml of glacial acetic acid and concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water, dried over magnesium sulphate, concentrated by evaporation and purified by flash chromatography on 700 g of silica gel 60 (eluant D). 1H-NMR (DMSO-d6): 1.35 ppm (t, 3H), 2.6-2.9 (m, 2H); 3.75 (dxd, 1H); 4.25 (q, 2H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([P:21](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24])([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[CH:4][N:3]=1.[NH:31]1[C:39]2[C:34](=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32]1>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.COCCOC>[NH:31]1[C:39]2[C:34](=[C:35]([C:2]3[CH:7]=[C:6]([CH2:8][C:9]([P:21](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24])([P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14])[F:10])[CH:5]=[CH:4][N:3]=3)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32]1
Reactant: CC(C)OP(=O)(OC(C)C)C(F)(Cc1ccnc(Cl)c1)P(=O)(OC(C)C)OC(C)C
Reactant: OB(O)c1cccc2[nH]ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CC(C)OP(=O)(OC(C)C)C(F)(Cc1ccnc(-c2cccc3[nH]ncc23)c1)P(=O)(OC(C)C)OC(C)C
Yield: 30.7 %

Procedure:
Tetraisopropyl (2-(2-chloropyridin-4-yl)-1-fluoroethane-1,1-diyl)bis(phosphonate) (78 mg; 0.16 mmol), Pd(PPh3)4 (37 mg; 0.032 mmol) and (1H-indazol-4-yl)boronic acid (52 mg; 0.32 mmol) are mixed in microwave vial (2-5 mL). The vial is capped with a septum, 2.0 mL of DME is added and the reaction mixture is immediately flushed with argon. Sodium carbonate solution (0.20 mL; 2M) is added and the mixture is flushed again with argon. The vial is re-capped with Teflon cap and irradiated in microwave for 15 min at 110° C. The mixture is cooled, diluted with EtOAc and filtered through Celite™, the Celite™ is rinsed 3× with EtOAc/MeOH (1:1). The filtrates are concentrated and deposited on silica. Purification by column chromatography on silica gel (pre treated with 1% NEt3 in hexanes) using a solvent gradient from hexanes to EtOAc, and then to 50% MeOH in EtOAc lead to the isolation of the product as a yellow oil (28 mg; 31% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[CH2:12]([O:15][C:16](Cl)=[O:17])[CH:13]=[CH2:14].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(NC(C2CC2)=O)C1)=O)CCC>>[CH2:12]([O:15][C:16]([NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)Cl
Reactant: NC1CNc2ccccc2C1
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(NC(=O)C2CC2)Cc2ccccc21)NC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CNc2ccccc2C1

Procedure:
In a manner analogous to that described in Example 109b) from 1.0 g of 1.0 g of 3(R,S)-amino-1,2,3,4-tetrahydroquinoline and 0.75 ml of allylchloroformate: Rf (P)=0.81; MS: M+ =232.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(O)C>[F:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCC[C@@H]1F
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1F
Yield: 91 %

Procedure:
Method 1 of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3S,4S)-4-fluoropiperidin-3-ylcarbamate and triethylamine in ethanol yielding tert-butyl (3S,4S)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (91%). LCMS (m/z): 341.0 (MH+); LC Rt=2.37 min.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:13]2[O:12][C:11](=[O:14])[C:10](=[O:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>ClCCl>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:11](=[O:14])[C:10](=[O:15])[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:13]=3[OH:12])=[CH:32][CH:33]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Reactant: CC(C)(C)c1cccc2c1OC(=O)C2=O
Solvent: ClCCl
Product: COc1ccc(CCc2ccc(NC(=O)C(=O)c3cccc(C(C)(C)C)c3O)cc2)cc1OC

Procedure:
A solution of 7-(1,1-dimethylethyl)-2,3-benzofurandione (1.0 g, 5 mmol) and 4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (1.0 g, 4 mmol) in 10 ml of dichloromethane is stirred at room temperature for 48 hours. The solvent is evaporated and the residue crystallized from ether/hexane. Recrystallization from acetonitrile gave the pure product, (1.0 g) mp 143°-144° C.