Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4](Cl)[N:3]=1.[CH3:16][C:17]1[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4]([NH:22][C:19]2[CH:18]=[C:17]([CH3:16])[NH:21][N:20]=2)[N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CN(c1nc(Cl)nc(Cl)c1F)S(C)(=O)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Cl)nc(N(C)S(C)(=O)=O)c2F)n[nH]1
Temperature: 50 °C
Yield: 94.5 %

Procedure:
To a solution of N-(2,6-dichloro-5-fluoropyrimidin-4-yl)-N-methylmethanesulfonamide (Method 31, 914 mg, 3.35 mmol) in n-BuOH (3 ml) was added 5-methyl-1H-pyrazol-3-amine (351 mg, 3.62 mmol, 97% purity) and DIPEA (1.2 ml, 6.9 mmol). The mixture was heated at 50° C. overnight. LC/MS showed the completion of the reaction. The solvent was evaporated and the residue was purified by silica gel chromatography (by ISCO Combiflash with gradient 0-5% methanol in DCM with 1% NH4OH) to afford the title compound as a light yellow solid (1.06 g, 95%). LC-MS, 335 (M+1). NMR (DMSO-d6, 400 MHz) δ12.27 (s, 1H), 10.53 (s, 1H), 6.32 (s, 1H), 3.27 (s, 3H), 3.20 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=O)C.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[N:11].[H-].[Na+].CO>O1CCCC1.C(O)(=O)C>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:6]2[CH2:7][CH2:8][NH:4][C:5]2=[O:9])=[CH:14][CH:13]=1)#[N:11]
Reactant: CC(=O)N1CCCC1=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1ccc(C=C2CCNC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
A solution of 5.0 g of N-acetyl-2-pyrrolidone and 5.17 g of 4-cyanobenzaldehyde in 50 ml of tetrahydrofuran is added dropwise to a suspension of 5.36 g of sodium hydride (55% in oil) in 50 ml of tetrahydrofuran at 5°-10° C. and the mixture is then stirred at 0° C. for 1 hour. Excess sodium hydride is eliminated by the addition of some methanol, and the reaction mixture is poured onto ice and neutralized with glacial acetic acid. The precipitate is suction-filtered and dissolved in a methylene chloride/methanol mixture, and the solution is dried and evaporated down. The residue is triturated with ether and suction-filtered. 1.4 g of 3-(4-cyanobenzylidene)-2-pyrrolidone are obtained as a colourless powder of melting point 260° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl.[O:42]=[C:43]1[NH:52][C:51]2[N:50]=[CH:49][C:48](/C=C/C(O)=O)=[CH:47][C:46]=2[CH2:45][CH2:44]1>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:42]=[C:43]1[NH:52][C:51]2[N:50]=[CH:49][C:48](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[CH:47][C:46]=2[CH2:45][CH2:44]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2

Procedure:
tert-Butyl acrylate (31.2 mL, 210 mmol), diisopropylethylamine (19.4 mL, 110 mmol) and P(o-tolyl)3 (3.2 g, 10.5 mmol) were successively added to a suspension of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (11.9 g, 52.5 mmol; which may be prepared as described in D1, Step 5) in propionitrile (83 mL) and dimethylformamide (46 mL). The resulting mixture was then purged with argon prior to the addition of palladium acetate (1.2 g, 5.2 mmol). The mixture was purged with argon again and refluxed overnight. The reaction mixture was then filtered on Celite®. The filtrate was concentrated to dryness and the residue was solubilized in ethyl acetate (200 mL). The resulting solution was washed with a saturated solution of sodium chloride (3×100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (98:2) as eluent. After trituration with Et2O/petroleum ether (1/1), the title product was obtained as a yellow solid (4.35 g, 40%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:19](=[O:20])[NH:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=1)[CH2:2]2
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: OC1CN2CCC1CC2
Product: O=C(Nc1ccc(Cl)c(Cl)c1)OC1CN2CCC1CC2
Yield: 60 %

Procedure:
3-Quinuclidinol and 3,4-dichlorophenyl isocyanate were used. Filtration of the precipitated solid from the cooled reaction mixture afforded the title compound (60%) as a white solid: mp 181.0-184.0° C.; FAB LRMS m /z (relative intensity, %) 319 ([MH+ with two Cl37 ], 13), 318 (11), 317 ([MH+ with one Cl37 ], 71), 316 (18), 315 ([MH+ with two Cl35 ], 100).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(S([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([C:25]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[N:28][N:27]4[CH2:36][CH2:37][CH2:38][C:26]=34)=[CH:17]2)(=O)=O)C=CC=CC=1.CO.O>C1(C)C=CC=CC=1>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[C:25]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:16][CH:17]=2)=[C:26]2[CH2:38][CH2:37][CH2:36][N:27]2[N:28]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: c1ccc(-c2nn3c(c2-c2c[nH]c4ccccc24)CCC3)nc1
Temperature: 25 °C

Procedure:
Add potassium carbonate (75 mg, 0.55 mmol) to a solution of 1-benzenesulfonyl-3-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole (120 mg, 0.27 mmol) in 3:1 methanol/water (1.2 mL). Reflux the reaction mixture for 16 h, cool to room temperature, and add toluene (50 mL). Concentrate in vacuo and purify by flash column chromatography, using the appropriate mixture of methylene chloride, chloroform, methanol, and concentrated aqueous ammonium hydroxide, to provide 6 mg (3% over 2 steps) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:22]([O:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[C:35](Cl)=[O:36])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:35]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:33]=[CH:34][C:25]=3[O:24][CH2:22][CH3:23])=[O:36])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ccccc2c1C(=O)n1cc(-c2ccc(OC)c(OC)c2)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 1 (638 mg, 2.51 mmole) was dissolved in DMF (30 mL) and sodium hydride (60% dispersion in mineral oil, 100 mg, 2.50 mmole) was added in small portions to the reaction mixture. After stirring for 30 minutes, 2-ethoxy-1-naphthoyl chloride (646 mg, 2.76 mmole) was added and the reaction was stirred for 4 hours. The reaction mixture was poured into 200 mL of ice water and was extracted with ethyl acetate. The organic layer was washed with saturated bicarbonate solution followed by saturated potassium hydrogen sulfate and then brine. The resulting solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate:hexanes) to yield 800 mg (70%) of the titled compound as a white solid MS(ESI) [M+H+]+=453.06.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2ccc(COC3CCCNC3)cc2)cc1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(OCc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Yield: 41.8 %

Procedure:
Using 3-[4-(4-fluorophenoxy)benzyloxy]piperidine (157 mg, 0.521 mmol) and 3-(methoxycarbonyl)phenylboric acid (187 mg, 1.04 mmol), the same procedure was followed as in Example 2 to give 94.8 mg (42%) of the desired compound as a colorless oil.
Reaction SMILES: C([O:8][CH2:9][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[O:11][CH3:12])C1C=CC=CC=1>[Pd].CO>[Si:15]([O:14][CH2:13][CH:10]([CH2:9][OH:8])[O:11][CH3:12])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(CO)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of the protected glycerol derivative 14 (5.0 g, 16 mmol) and 10% palladium on activated carbon (wet Degussa type E101 NE/W) (0.43 g) in MeOH (50 mL) was evacuated using an aspirator pump and filled with hydrogen. After 2 h, TLC analysis showed the reaction to be complete, the mixture was filtered through Celite and the filtrate was evaporated to dryness to give 1-O-t-butyldimethylsilyl-2-O-methyl-rac-glycerol (15) (99%) as a colourless oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=1>CS(C)=O.C(OCC)(=O)C>[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[C:35]1[CH2:36][CH2:37][N:38]([CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)[CH2:39][CH:40]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CC2
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccc(F)cc34)CC1)CC2
Temperature: 80 °C
Yield: 69.1 %

Procedure:
To a solution of [(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.348 g, 1.00 mmol) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.865 g, 4.00 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) followed by recrystallization from ethanol provided 0.271 g (69%, 40% ee) of 5-fluoro-3-(1-{[(2R)-8-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a tan crystalline powder. [α]D25=−22.05 (c 9.98 in chloroform, 40% ee); Rf=0.49 (silica, ethyl acetate:hexanes 4:1); mp 177-180° C. dec; Anal. Calcd. for C24H25FN2O2: C, 73.45; H, 6.42; N, 7.14. Found: C, 73.03; H, 6.49; N, 7.12.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([SH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(O[CH:17]1[NH:20][C:19](=[O:21])[CH2:18]1)(=O)C>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([S:12][CH:17]2[NH:20][C:19](=[O:21])[CH2:18]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(S)cc1OC
Reactant: CC(=O)OC1CC(=O)N1
Agent: [Na]
Solvent: CCO
Product: COc1ccc(SC2CC(=O)N2)cc1OC
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Sodium (0.9 g, 39 mmol) was dissolved in ethanol (150 ml) and 3,4-dimethoxythiophenol (5.9 g, 35 mmol) added dropwise over 20 minutes keeping the temperature between 20° C.-25° C. whilst bubbling nitrogen through the mixture. After 15 minutes, the reaction was cooled to 5° C. and a solution of 4-acetoxyazetidin-2-one (4.3 g, 33 mmol) in ethanol (50 ml) was added dropwise over 15 minutes whilst maintaining the temperature at 5° C. The mixture was stirred at room temperature for 60 minutes and evaporated to dryness under reduced pressure. Water (400 ml) was added, the mixture extracted with dichloromethane (2×300 ml), the extracts dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was cooled to -20° C. and titurated with ether (400 ml) to give a white solid which was isolated by filtration (4.1 g, 52%) m.p. 145-6° C. 1H NMR δ (CDCl3) 2.85 (1H, m, H3a), 3.31 (1H, m, H3b), 3.88 (3H, s, O--CH3), 3.89 (3H, s, O--CH3), 4.92 (1H, dd, J=4.92, 2.30 Hz, H4), 6.30 (1H, br. singlet, N--H), 6.85 (1H, d, J=8.30 Hz, Ph--H), 7.00 (1H, d, J=2.04 Hz, Ph--H), 7.09 (1H, dd, J=8.25, 2.06 Hz, Ph--H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][C@@H:19]2[F:35])([CH3:17])[C:15](=[O:36])[CH2:14][CH2:13]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C>[F:35][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:36])[C@H:11]2[C@H:20]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:25][C:26]=1[CH2:27][C@H:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(OC3CCCCO3)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(OC5CCCCO5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
7.4 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-17-one in 370 ml of methanol and 37 ml of water is stirred at room temperature with 1.8 g of potassium carbonate. After 3 hours, the reaction mixture is added to ice water. The precipitated product is suctioned off, dissolved in ethyl acetate, washed neutral with water, dried and concentrated by evaporation in a vacuum. 7.0 g of 11β-fluoro-7α-(5-hydroxypentyl)-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-17-one is obtained as foam.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31](Cl)=[O:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>C1COCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:1][C:2](=[O:11])[CH2:3]2)=[O:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(/C=C/C(=O)Cl)cc1OC
Reactant: O=C1CNc2ccccc2N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/C(=O)N2CC(=O)Nc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a stirred solution of 3,4-dihydroquinoxalin-2(1H)-one (142 mg, 0.96 mmol) and triethylamine (0.16 mL, 1.14 mmol) in anhydrous THF (15 mL) at 0° C. was added a solution of (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride in THF (2 mL) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by addition of 1N hydrochloric acid, and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product which was purified by flash chromatography (hexane-EtOAc, 25:10) to give (E)-4-(3-(3,4-dimethoxyphenyl)acryloyl)-3,4-dihydroquinoxalin-2(1H)-one (160 mg, 47%). 1H-NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 3.90 (s, 3H), 4.63 (br s, 2H), 6.71 (d, J=15.2 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 7.02 (dd, J=7.6, 1.2 Hz, 1H), 7.07-7.13 (m, 2H), 7.22 (dd, J=7.6, 1.2 Hz, 1H), 7.28 (br d, J=8.0 Hz, 1H), 7.76 (d, J=15.6 Hz, 1H), 8.89 (s, 1H); LC-MS (ES-API); rt 8.14 min; m/z calculated for C19H18N2O4[M+H]+ 339.1, found 339.0.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[C:18]([NH:20][C:21]([C:26]#[N:27])([CH:23]3[CH2:25][CH2:24]3)[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:33].C1C([N+]([O-])=O)=CC=C([Cl-][C:44]([O-])=[O:45])C=1.[CH:47]1([CH2:50][NH2:51])[CH2:49][CH2:48]1>ClCCl>[C:26]([C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:28]=[CH:29][CH:30]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:31]=[CH:32][C:2]([NH:1][C:44]([NH:51][CH2:50][CH:47]4[CH2:49][CH2:48]4)=[O:45])=[C:3]([F:33])[CH:4]=3)[CH2:13][CH2:12]2)[CH:16]=1)([CH:23]1[CH2:25][CH2:24]1)[CH3:22])#[N:27]
Reactant: CC(C#N)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1)C1CC1
Reactant: NCC1CC1
Solvent: ClCCl
Product: CC(C#N)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)c(F)c3)CC2)c1)C1CC1
Reaction time: 0.5 h
Yield: 42 %

Procedure:
3-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-yl)methyl)—N-(1-cyano-1-cyclopropyl-ethyl)benzamide (49 mg, 0.109 mmol) was stirred In dichloromethane at room temperature. 4-Nitrophenylchloroformate (22 mg, 0.109 mmol) was added and the reaction mixture stirred for 30 minutes. Cyclopropylmethylamine (23 mg, 0.327 mmol) was added and the reaction allowed to stir for 30 minutes at room temperature. The reaction was concentrated under reduced pressure and the resulting residue purified by silica column chromatography to afford the title compound (25 mg). MS (ESI) m/z 547.5 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:5][C:4]=1[N+:18]([O-])=O.C([O-])([O-])=O.[Na+].[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+].CC(OO)=O>CCO.O>[CH3:1][NH:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:5][C:4]=1[NH2:18]
Reactant: CNc1ccc(Oc2ccnc(C#N)c2)cc1[N+](=O)[O-]
Agent: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: CCO
Solvent: O
Product: CNc1ccc(Oc2ccnc(C#N)c2)cc1N
Temperature: 41.70000076293945 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carbonitrile (5.0 g, 0.019 moles) in EtOH (15 mL) was heated to 40° C. Na2CO3 (4.7 g, 0.044 moles) was added followed by H2O (8.4 mL). Na2S2O4 (3.3 g, 0.019 moles) was added followed by H2O (10 mL). The temperature rose from 41.7 to 49.5° C. After cooling down to 41.7° C., Na2S2O4 (3.3 g, 0.019 moles) was added followed by H2O (10 mL). The temperature rose to 44.5° C. After cooling down to 36.7° C., Na2S2O4 (6.6 g, 0.038 moles) was added followed by H2O (20 mL). The temperature rose to 44.0° C. HPLC analysis showed 4.1% (LCAP) of the starting material. Additional Na2S2O4 (3.3 g, 0.019 moles) was added. After stirring an additional 15 min, heat was removed and H2O (12.5 mL) was added. At 25° C., additional Na2CO3 (1.3 g, 0.012 moles) was added and the mixture cooled in an ice/water bath. At less than 5° C., the mixture was allowed to age for 30 min (final temperature of 1.5° C.). The solid was collected by filtration and washed with H2O (10 mL followed by 5 mL). The solid was dried on the filter for 30 min and then transferred to the reaction flask and H2O (50 mL) added. The mixture was stirred for 45 min. The solid was then collected by filtration and washed with H2O (2×10 mL). The crude product was dried in a vacuum oven at 50° C. for 16 h to afford 3.50 g (76%) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.5 (m, 1H), 7.5 (m, 1H), 7.1 (m, 1H), 6.4 (m, 1H), 6.3 (m, 2H), 4.8 (s, 2H), 4.7 (s, 1H), 2.7 (s, 3H); APCI MS [M+H]+=241; HPLC >99% (LCAP).
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14]>>[CH3:10][O:9][C:7](=[O:8])[C:6]([CH2:12][C:13](=[O:14])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
57.2 g (1.06 mols) of sodium methylate are suspended in 400 g of dehydrated pinacolin. 118 g of molten oxalic acid dimethyl ester are added dropwise to the suspension in the course of 1 hour. The temperature is kept at 10° C. during this addition. The mixture is subsequently stirred for 15 minutes and 84 g of a methanol/pinacolin mixture are then distilled off at 64° C. The bottom product is cooled to 50° C. and 252 g of aqueous sulphuric acid (20.9% strength by weight) are added. Separation of the phases and subsequent distillation of the organic phase gives 164.6 g of pivaloylpyruvic acid methyl ester (87.8% of the theoretical yield), purity: 99.3%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:7]([N:6]([CH2:5][C:4]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:3]=1[O:2][CH3:1])[C:26](=[O:27])[CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCCCNCc1cccc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Yield: 120.6 %

Procedure:
N-(2,3-dimethoxybenzyl)butan-1-amine (0.59 g, 2.65 mmol) was dissolved in DMF (10 ml), 3-(4-hydroxyphenyl)propanoic acid (0.4 g, 2.41 mmol), was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.85 g, 2.65 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol) was added. The mixture was allowed to warm to room temperature and stirred over night. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). EtOAc was removed by evaporation and the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two potions of brine and dried (MgSO4). The solvent was removed by evaporation and gave 1.08 gram of N-butyl-N-(2,3-dimethoxybenzyl)-3-(4-hydroxyphenyl)propanamide (yield 82.3%).
Reaction SMILES: [CH2:1]([C@@:8]1([O:16][C@H:15]([CH2:17][NH:18][C:19]([C@@H:21]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[OH:22])=[O:20])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:10]1[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[CH2:1]([C@@:8]1([O:16][C@H:15]([CH2:17][NH:18][C:19]([C@@H:21]([C@@H:23]([C@@H:25]([CH2:27][O:28][C:8](=[O:9])[CH3:1])[O:26][C:11](=[O:12])[CH3:10])[O:24][C:19](=[O:20])[CH3:21])[O:22][C:23](=[O:24])[CH3:25])=[O:20])[C@@H:13]([O:14][C:33](=[O:32])[CH3:34])[C@H:11]([O:12][C:13](=[O:14])[CH3:15])[C@H:10]1[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CNC(=O)[C@H](O)[C@H](O)[C@H](O)CO)O[C@@]1(O)Cc1ccccc1)OCc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)C(=O)NC[C@H]1O[C@@](O)(Cc2ccccc2)[C@H](NC(=O)OCc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
D-Ribonic acid (benzyl 2-benzyloxycarbonylamino-2,6-didesoxy-α-D-glucopyranosid-6-yl)-amide was acetylated as described in Ex. 14.B. and gave 2,3,4,5-tetra-O-acetyl-D-ribonic acid (benzyl 3,4-di-O-acetyl-2-benzyloxycarbonylamino-2,6-didesoxy-α-D-glucopyranosid-6-yl)-amide, [α]+78.0° (c 0.2; dioxan), MS: m/z 803.2 ([M+H]+).