Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:24][C:25]([NH2:28])([CH3:27])[CH3:26].CO.C(Cl)Cl>CS(C)=O>[C:25]([NH:28][C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:27])([CH3:26])[CH3:24]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1NC(C)(C)C
Temperature: 100 °C
Yield: 53.6 %

Procedure:
2-(3-(tert-Butylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one enantiomers were prepared similar to that described in Example 131 using rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 69.4 mg, 0.224 mmol) and 2-methylpropan-2-amine (TCI America, Portland, Oreg.; 0.071 mL, 0.671 mmol) in DMSO (1.0 mL), heating 100° C. for 1.5 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished rac-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (43.6 mg, 0.120 mmol, 54% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (1H, br. s.), 7.79 (1H, d, J=7.4 Hz), 7.59 (1H, d, J=8.2 Hz), 7.33 (1H, t, J=7.8 Hz), 6.95 (1H, s), 6.92 (1H, br. s.), 5.97 (1H, s), 3.45-3.55 (1H, m), 3.01-3.14 (2H, m), 2.55 (3H, s), 1.54 (9H, s), 1.27 (3H, d, J=6.3 Hz). m/z (ESI, +ve) 364.2 (M+H)+. Separation of this material by supercritical-fluid chromatography (Chiralpak AS-H (250×21 mm, 5 μm), 70% liquid CO2/30% MeOH (+20 mM NH3), 70 mL/min) separately afforded: 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, first-eluting enantiomer (162; 17.4 mg, 0.048 mmol) as a yellow solid; and 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, second-eluting enantiomer (163; 16.4 mg, 0.045 mmol) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:31](I)[CH3:32].CN(C)C=O>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:31][CH3:32])=[O:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C(O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
A mixture of 6.4 g of 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid, 3.1 g of sodium hydrogencarbonate, 8.6 g of ethyl iodide and 20 ml of N,N-dimethylformamide is heated at 100° C. with stirring for 3 hours. Further, 2.9 g of ethyl iodide and 1 g of sodium hydrogencarbonate are added to the reaction solution, followed by heating at 100° C. for 2.5 hours. After cooling, 200 ml of water is added to the reaction solution, and the mixture is extracted with 300 ml of ethyl acetate. The extract is washed with water, 0.1 N hydrochloric acid and dilute aqueous sodium hydrogen-carbonate solution successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5 g of ethyl 7-(1-benzyloxycarbonyl-4piperidyl)heptanoate as an oily material.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C-:13]#[N:14].[C-]#N.[Na+].C(OCC)(=O)C>O>[C:13]([C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])#[N:14]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1C#N
Temperature: 195 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), cupper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrrolidinone (30 mL). After heating at 195° C. for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 106a in 73% yield (6.99 g) as a white solid: mp 92-93° C.; 1H NMR (500 MHz, CDCl3) δ 8.18 (dd, 1H, J=9.0, 5.5 Hz), 7.50 (dd, 1H, J=8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)[CH3:3].[C:16]1([NH:22]C(N)=N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[N:27](C=O)C>>[N:27]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][CH2:14][C:5]=2[CH:4]=[N:2][C:3]=1[NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=C1CCc2ccccc2C1=O
Reactant: N=C(N)Nc1ccccc1
Reactant: CN(C)C=O
Product: c1ccc(Nc2ncc3c(n2)-c2ccccc2CC3)cc1

Procedure:
A solution of 2-dimethylaminomethylene-3,4-dihydro-2H-naphthalen-1-one 100 mg in 5 ml DMF and 3 eq. of N-phenyl-guanidine was stirred at 110° C. for overnight, the product was purified by directly injecting the DMF reaction solution into prep HPLC.
Reaction SMILES: [C:1]([Cl:5])(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>CC(C)=O>[ClH:5].[C:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: Nc1cc(C(=O)c2ccccc2)ccc1N1CCOCC1
Solvent: CC(C)=O
Product: CCC(=O)Nc1cc(C(=O)c2ccccc2)ccc1N1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.2 g. of propionyl chloride in 50 ml. of acetone is added dropwise, at room temperature to a stirred solution of 28 g. of 3-amino-4-morpholino-benzophenone in 560 ml. of acetone. After the addition the reaction mixture is stirred for additional 30 minutes at room temperature. The separated crystalline 3-pripionyl-amino-4-morpholino-benzophenone hydrochloride is filtered off, and washed with ether. 34 g. of the aimed compound are obtained; m.p.: 152°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Yield: 33.4 %

Procedure:
A mixture of 10 g (0.06 mol) of 3,5-dihydroxybenzoic acid methyl ester, 16.2 ml (0.06 mol) of 1-bromotetradecane and 8.2 g (0.06 mol) of potassium carbonate in 200 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 24 hours, After the usual workup, the crude product was triturated with hot methylene chloride and filtered. The filtrate was concentrated at reduced pressure and the solid residue was recrystallized from methylene chloride-methanol to give the 3,5-dialkylated product. The filtrate was concentrated and the residue was purified by HPLC using 15% ethyl acetatehexane to give 7.3 g (34% yield, mp 92°-94°) of 3-hydroxy-5-(tetradecyloxy)benzoic acid methyl ester. The nmr spectra was consistent with the structure.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH:27]1([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[C:37]5[C:32](=[CH:33][CH:34]=4)[C:31](=[O:48])[N:30]([CH:27]4[CH2:29][CH2:28]4)[CH2:38]5)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.0209 g, 0.0500 mmol), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (0.0194 g, 0.0650 mmol), in 1,4-dioxane (0.30 mL) was stirred at r.t. for 10 min. Potassium carbonate (27.6 mg, 0.200 mmol) in water (0.15 mL) was added. The mixture was degassed and refilled with nitrogen three times. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.5 mg, 0.0030 mmol) was added The mixture was degassed and refilled with nitrogen three times, and heated at 120° C.) (oil bath temperature) for 1 h. After cooling, the mixture was diluted with methanol, and filtered. The filtrate was purified on RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=510.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH:18]([CH3:20])[CH3:19])[N:14]([CH3:21])[C:13]=2[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][NH:43][CH3:44].[C:45](=[O:47])=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:42][N:43]([CH3:44])[C:45]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[N:16]=[C:15]([CH:18]([CH3:20])[CH3:19])[N:14]([CH3:21])[C:13]=2[CH:12]=1)=[O:47]
Reactant: O=C=O
Reactant: CNC
Reactant: CC(C)c1nc2c(OCc3ccccc3)cc(Br)cc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)c1nc2c(OCc3ccccc3)cc(C(=O)N(C)C)cc2n1C
Yield: 70 %

Procedure:
5.6 g (15.5 mmol) 4-Benzyloxy-6-bromo-2-isopropyl-1-methyl-1H-benzimidazole, 2.4 g (3.3 mmol) triphenylphosphine, 521 mg (2.3 mmol) palladium(II) acetate and 78.5 ml (155 mmol) dimethylamine (2 M in THF) were transferred to an autoclave and carbonylated (6 bar CO2) at 120° C. for 3 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel (petroleum ether/ethyl acetate=1:5) afforded 3.8 g (70%) of the title compound as a yellow wax.
Reaction SMILES: [CH3:1][CH:2]([CH:5]([CH3:11])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=O.[CH:12](=[O:15])[CH2:13][CH3:14]>>[CH3:14][CH:13]([CH2:3][CH:2]([CH3:1])[CH:5]([CH3:11])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:12]=[O:15]
Reactant: CCC=O
Reactant: CC(C=O)C(C)CC(C)(C)C
Product: CC(C=O)CC(C)C(C)CC(C)(C)C

Procedure:
2,4,5,7,7-Pentamethyloctanal was prepared from 2,3,5,5-tetramethylhexanal (aldehyde of TMH from Dragoco, Holzminden) and propionaldehyde similarly to Examples 1 and 2; the compound was obtained in the form of a diastereomeric mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(O)C.C1(C)C=CC=CC=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.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>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=2)[CH:20]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1cccc(Br)c1
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+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To 3-bromoaniline (513.1 mg, 2.983 mmol) was added ethanol/toluene (1:1, 20 mL), 3-pyridinylboronic acid (397.3 mg, 3.232 mmol), sodium carbonate (1.85 g, 17.45 mmol) in 9 mL water, and tetrakis(triphenylphosphine)palladium (504.3 mg, 0.439 mmol). The resulting mixture is heated to 80° C. and stirred for 16 h. The reaction mixture is cooled, diluted with 10 mL of water and extracted with EtOAc (3×25 ml). The organics were combined and, washed with 10 mL of water and saturated aqueous NaCl (2×10 mL), then dried over magnesium sulfate and concentrated in vacuo to a brown oil. The oil is purified over silica (0-5% MeOH in CH2Cl2) to afford 345 mg (68% yield) of the desired compound. MS (ESI, pos. ion) m/z: 171 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: CCNCC(=O)O
Reactant: Cc1ccc(N=C=S)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2ccc(C)cc2C)C1=S
Yield: 43.6 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 16.3 g of 2,4-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethanol afforded the title compound (10.8 g) as a light peach solid, m.p. 161°-162° C. Anal. Calcd. for. C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.63; H, 6.45; N, 11.17. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [CH2:1]([C:3]1([CH2:12][CH3:13])[CH:8]([NH2:9])[CH2:7][CH2:6][CH2:5][C:4]1([CH3:11])[NH2:10])[CH3:2]>[Pt].CC(C)=O>[CH:1]([NH:10][C:4]1([CH3:11])[CH2:5][CH2:6][CH2:7][CH:8]([NH:9][CH:4]([CH3:11])[CH3:5])[C:3]1([CH2:1][CH3:2])[CH2:12][CH3:13])([CH3:3])[CH3:2]
Reactant: CCC1(CC)C(N)CCCC1(C)N
Agent: [Pt]
Solvent: CC(C)=O
Product: CCC1(CC)C(NC(C)C)CCCC1(C)NC(C)C
Temperature: 120 °C
Yield: 95 %

Procedure:
Diethyl(methyl)-1,3-cyclohexanediamine, as a mixture of its 2,4-diethyl-6-methyl- and 4,6-diethyl-2-methyl-isomers was made as described in Example 4. Diethyl(methyl)-1,3-cyclohexanediamine, as a mixture of its 2,4-diethyl-6-methyl- and 4,6-diethyl-2-methyl-isomers (10 g), Pt(S)/C (0.5 g), Amberlyst-15 (0.5 g), and acetone (50 g) were charged into a 100 mL metal autoclave at 22° C. The closed autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. to remove traces of air. The reaction mixture was then heated at 110-130° C. under 125 psig (9.63×105 Pa) of H2 for 8 hrs (until no further H2 uptake was observed). The product mixture was cooled to 22° C. and degassed. A diluted product sample was analyzed by GC (100° C. for 5 minutes at 10° C. per minute rate; final temperature, 270° C.). The GC data (normalization method) showed 100% conversion of diethyl(methyl)-1,3-cyclohexanediamine, and a 95-97% yield of N,N′-diisopropyl-[diethyl(methyl)-1,3-cyclohexanediamine].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(O[CH2:30][CH:31]([CH3:33])[CH3:32])=O.C[CH:35]1CC(C)C[CH:37]([NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[CH2:36]1>C1COCC1>[CH3:32][CH:31]1[CH2:33][CH:36]([CH3:35])[CH2:37][N:42]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([NH:50][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)=[CH:48][CH:49]=2)[CH2:30]1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC1CC(C)CC(NCc2ccc(N)cc2)C1
Reactant: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC1CC(C)CN(Cc2ccc(NC(=O)C#Cc3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1

Procedure:
A solution of 0.26 g (1 mmol) of (4′-chlorobiphenyl-4-yl)propynoic acid and 0.12 mL (1.1 mmol) of N-methylmorpholine in 20 mL of absolute THF is combined with 0.14 mL (1.1 mmol) of isobutyl chloroformate at −15° C. and stirred for ten minutes. Then 0.240 mg (1.1 mmol) of 4-[(3,5-dimethylcyclohexylamino)methyl]phenylamine dissolved in 7 mL of THF is added and the reaction mixture is stirred for 16 hours. The reaction mixture is evaporated down. The purification is carried out by column chromatography on silica gel (dichloromethane/methanol=90/10). Yield: 300 mg (66% of theory); melting point: 209° C.-214° C.; C29H29ClN2O (M=457.01); calc.: molecular ion peak (M+H)+: 457/459 (Cl); found: molecular ion peak (M+H)+: 457/459 (Cl); Rf value: 0.60 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[S:11][CH:12]=[C:13]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[N:14]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:20][C:15]1([C:13]2[N:14]=[C:10]([CH2:9][OH:8])[S:11][CH:12]=2)[O:19][CH2:18][CH2:17][O:16]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(C2(C)OCCO2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2csc(CO)n2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)-thiazole (1.30 g, 4.12 mmol) in dry THF (10 mL) was treated at 0° C. with TBAF (6.2 mL of a 1M solution in THF, 6.20 mmol). The reaction mixture was stirred at 0° C. for 5 min and at rt for 1 h 30. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (5:1->1:3 hept-EA) gave the title compound as a yellow oil. TLC:rf (1:2 hept-EA)=0.20. LC-MS-conditions 02: tR=0.59 min; [M+H]+=202.48.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=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][CH3:14].[CH:24]1[C:29]2[C:30]([O:32][C:33](=O)[C:28]=2[CH:27]=[N:26][CH:25]=1)=[O:31]>C(Cl)(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:30](=[O:31])[C:29]3[CH:24]=[CH:25][N:26]=[CH:27][C:28]=3[C:33]2=[O:32])=[CH:18][CH:17]=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][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(CN)cc1
Reactant: O=C1OC(=O)c2cnccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(CN2C(=O)c3ccncc3C2=O)cc1
Temperature: 190 °C
Yield: 88.5 %

Procedure:
A mixture of 2.5 g of product from Example 99 and 1.17 g of 3,4-pyridinecarboxylic anhydride is heated, in a sealed tube, at 190° C. for 12 minutes. The cooled crystalline product is dissolved in chloroform, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel: 30-40% ethyl acetate/hexane) to give 3.12 g of the desired product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:11]2[C:12](=[CH:20]O)[C:13](=O)[CH2:14]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)(=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:11]2[C:12]2[CH:20]=[N:23][NH:24][C:13]=2[CH2:14]3)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)s1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccc(Cl)s1)N1C2CCCC1c1cn[nH]c1C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 9-(5-chloro-thiophene-2-sulfonyl)-2-hydroxymethylene-9-aza-bicyclo[3.3.1]nonan-3-one crude mixture in glacial acetic acid (3 mL) followed by hydrazine monohydrate (1 mL). The reaction mixture was stirred at 100° C. for 1 h after which the solution was cooled to room temperature and quenched by the addition of saturated NaHCO3 solution (until pH>7). The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography (Elution with 50% EtOAc/hex, 80% EtOAc/hex, 100% EtOAc, and 5% MeOH/EtOAc) and preparative HPLC to give 12-(5-chloro-thiophene-2-sulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.649 min, Method 1, MS (ESI) 344.0 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 7.25 (s, 1H), 7.22 (d, =4.4 Hz, 1H), 5.28 (b s, 1H), 4.56 (t, J=6.04 Hz, 1H), 3.11 (dd, J=17.58, 7.69 Hz, 1H), 2.66 (d, J=17.58 Hz, 1H), 2.09-1.92 (m, 2H), 1.74-1.57 (m, 3H), 1.44-1.29 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 143.4, 139.2, 137.7, 131.8, 127.4, 127.0, 117.0, 48.0, 47.9, 32.3, 31.7, 25.4, 15.3 ppm.
Reaction SMILES: [Se](=O)=O.[F:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1.CC(=[N:17][OH:18])C>O.O1CCOCC1>[F:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH:12]=[N:17][OH:18])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)c1cccc(F)c1
Reactant: CC(C)=NO
Agent: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(C=NO)c1cccc(F)c1
Reaction time: 24 h

Procedure:
To a mixture of selenium dioxide (58.3 g, 525 mmol) in 20 ml of water and 400 ml of 1,4-dioxane was added in one-portion 1-(3-fluoro-phenyl)-ethanone (69.0 g, 500 mmol). The mixture was refluxed overnight, then filtered through diatomaceous earth. The filtrate was added to an equal volume of water and adjusted to pH 4 with 5% aqueous sodium hydroxide. To this mixture was added acetone oxime (40.2 g, 550 mmol) and the mixture was stirred for 24 h. On dilution to 1.5 L with water, the mixture was extracted with ethyl acetate (2×400 ml), and the organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated to give a oil residue, which was purified by flash chromatography on silica gel (eluting with pure Petroleum) to return title compound as a pale yellow solid (68.0 g, 81.4%). 1H NMR (DMSO-d6): δ 12.78 (s, 1H), 8.02 (s, 1H), 7.82-7.50 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N+](=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N-]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][O:17][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C(c2ccc(Cl)c(Cl)c2)C1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)COCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
Under a nitrogen atmosphere at 80° C., to a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (600 mg) and rhodium acetate dimer (7 mg) in toluene (5 ml) was added dropwise a solution of ethyl diazoacetate (860 mg) in toluene (5 mL) over 10 min. The reaction mixture was stirred at the same temperature for 10 min. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (615 mg).