Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([O-])=O.ClC1C(=O)C(C#N)=C(C#N)C(=[O:19])C=1Cl.O1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:8]([C:9]1[NH:10][C:2](=[O:1])[CH:3]=[CH:4][C:30]=1[C:29]([O:28][CH2:27][CH3:26])=[O:19])[CH3:7]
Reactant: C1COCCO1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C([O-])C1C=CC=NC1=O
Product: CCOC(=O)c1ccc(=O)[nH]c1CC

Procedure:
A mixture of the above oxonicotinate (2.7 g, 13.7 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in 100 ml of dioxane is heated to reflux overnight, after which the dioxane is removed by rotoevaporation The residue is dissolved in chloroform and extracted with sat. sodium bicarbonate. The organic fraction is washed with brine and dried and the solvent is removed. The resulting solid is triturated with small volumes of ether/hexane. The solid left undissolved is dried to give ethyl 1,6-dihydro-2-ethyl-6-oxonicotinate.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]2[CH2:21][C@@H:7]1[CH2:8][CH2:9]2)=O)C.[Na].[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([CH2:34][C:35]([O-])=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Br:23][C:24]1[CH:39]=[N:38][C:27]2[NH:28][C:29]([C:34]3[C:35](=[O:36])[N:12]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[C@@H:11]4[C@H:6]([C:4]=3[OH:3])[C@@H:7]3[CH2:21][C@H:10]4[CH2:9][CH2:8]3)=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1
Reactant: O=C([O-])CC1=NS(=O)(=O)c2cc(Br)cnc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C(C2=NS(=O)(=O)c3cc(Br)cnc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reaction time: 0.02 h
Yield: 60.3 %

Procedure:
(1S,2R,3S,4R)-3-(4-Fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 61, 0.213 g, 0.73 mmol), sodium-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-acetate (0.25 g, 0.73 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.305 g, 0.803 mmol) were combined and dissolved in N,N-dimethylformamide (1.5 mL). The mixture was shaken vigorously for about 1 min until everything dissolved. The solution continued to stir for 1 h. Triethylamine (0.5 mL, 3.65 mmol) was added and the mixture was stirred at 50° C. for 16 h. The mixture was concentrated in vacuo to a volume of ˜5 mL. Water (˜20 mL) was added and the product precipitated. The solid was collected by vacuum filtration and purified by flash column chromatography (Merck silical gel 60, 40-63 μm; 35% ethyl acetate in hexanes) to afford the desired product, (0.24 g, 0.44 mmol, 60%) as a white, brittle foam. A portion of the product (0.07 g, 0.128 mmol) was recrystallized from n-propanol (0.5 mL) to afford the pure desired product, 5-(7-bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.044 g, 0.081 mmol, 63%), as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.23 (2H, m), 1.38-1.60 (4H, m), 2.51 (1H, s), 2.63 (1H, s), 3.00 (1H, d, J=8.4 Hz), 3.55 (1H, d, J=9.4 Hz), 4.41 (1H, d, J=14.7 Hz), 4.95 (1H, d, J=15.4 Hz), 7.14 (2H, t, J=9.0 Hz), 7.33 (2H, dd, J1=8.6 Hz, J2=5.5 Hz), 8.66 (1H, s), 8.82 (1H, s). LC-MS (ESI) calcd for C23H20BrFN4O4S 546.04. found 547.2 [M+H+].
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]1C[O:13][CH2:12][CH2:11]1.BrC(F)(F)C(OCC)=O.C(=O)CC.C1COCC1.C(=O)CC.C(OC(C)C)(C)C>[Zn].O.C1COCC1>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[CH:12]([OH:13])[CH2:11][CH3:10])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C1CCOC1
Agent: [Zn]
Solvent: CCC=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCOC(=O)C(F)(F)C(O)CC
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A 500 mL reactor was charged with 24.2 g (370 mmol/1.5 equivalents) of an activated metal zinc and 300 mL of THF (dehydrated), and thereto an ethyl bromodifluoroacetate/THF solution [51.47 g (253.6 mmol/1.0 equivalent) of ethyl bromodifluoroacetate and 80 mL of THF (dehydrated)] was added dropwise. After the dropping, stirring was conducted at room temperature for 20 minutes. Then, a propionaldehyde/THF solution [14.80 g (254.8 mmol/1.0 equivalent) of propionaldehyde and 80 mL of THF (dehydrated)] was added, followed by stirring at room temperature for 30 minutes. Then, water and diisopropyl ether were added to conduct a two-layer separation. The obtained organic layer was washed with diluted hydrochloric acid and water, followed by removing water by magnesium sulfate, conducting a filtration, and distilling diisopropyl ether out, thereby obtaining 41.2 g of the target 2,2-difluoro-3-hydroxypentanoic acid ethyl ester. Upon this, yield was 89%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:5]=1[NH2:6].[C:15](Cl)(Cl)=[O:16]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:4]([O:3][CH3:2])[C:5]=1[N:6]=[C:15]=[O:16]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(N=C=O)c(OC)c1
Temperature: 95 °C
Reaction time: 48 h

Procedure:
A suspension of 2,4,6-trimethoxyaniline hydrochloride (71.1 g, 0.324 mol) in a 12.5% wt/wt solution (540 mL) of phosgene in toluene was heated (95° C.) for 3 hours. Additional phosgene solution (2×270 mL) was added every hour. The mixture was allowed to cool and stirred under house vacuum for 2 days. The mixture was rotoevaporated to a solid. The solid was triturated with ether (450 mL), filtered, and the filtrate rotoevaporated to give a purple amorphous solid; yield 66.9 g (99%); mp 67°-70° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:30]([O:37][C:38](=[O:44])[C@@H:39]1[CH2:43][CH2:42][CH2:41][NH:40]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.C(Cl)(Cl)Cl>[CH2:30]([O:37][C:38](=[O:44])[C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 8 h

Procedure:
Boc-L-alanine (19.5 g, 0.10 mol) was dissolved in dry tetrahydrofuran (90 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and an internal thermometer. The solution was cooled to -15° C. and N-methylmorpholine (11.4 ml, 0.10 mol) was added followed by isobutylchloroformate (13.4 ml, 0.10 mol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Five minutes after the addition was completed, a solution of L-proline benzyl ester hydrochloride (25.2 g, 0.10 mol) and N-methylmorpholine (11.4 ml, 0.10 mol) in chloroform (90 ml) was added dropwise at such a rate as to maintain the internal reaction temperature at -10° to -15° C. After the addition was completed, the reaction mixture was allowed to slowly warm to room temperature and then stirred at room temperature overnight. The reaction mixture was concentrated using a rotary evaporator, the residue diluted with ethyl acetate (500 ml)/0.2N hydrochloric acid (100 ml) and poured into a separatory funnel. The layers were separated and the aqueous phase extracted with a further 150 ml ethyl acetate. The combined organics were washed with 0.2 N hydrochloric acid (2×100 ml), water (100 ml), saturated sodium bicarbonate (2×100 ml), again with water (100 ml) and finally brine (100 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. Chromatography using ethyl acetate-hexane as the eluent gave Boc-L-alanyl-L-proline benzyl ester, Rf: 0.15 (EtOAc/hexane--30:70).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].C(N(CC)CC)C.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[Si:21]([NH:3][CH:2]([CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(N)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(N[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of racemic α-methyl-benzenemethanamine (24.2 g, 0.2 mol) and triethylamine (42 mL, 0.30 mol) in acetonitrile (400 mL) in a flame-dried flask under nitrogen was added dropwise t-butylchlorodiphenylsilane (47 mL, 0.18 mol). The mixture was stirred at room temperature for 3 hours and then filtered to remove the insoluble white precipitate (triethylamine hydrochloride). After removal of the solvent in vacuo, the crude product was taken up in ether and washed sequentially with H2O, saturated NaHCO3 solution and brine. The solution was dried (Na2SO4 /K2CO3) and concentrated to leave a clear oil which was distilled under high vacuum. The major fraction consisting of the pure title compound (30.5 g, 47%) distilled from 160° to 165° C. at about 0.4 mm Hg.
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][C:27]=1[F:33].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:28][C:27]=1[F:33]
Reactant: COC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.085 g, 0.3 mmol), methyl-2-fluoro-4-iodophenylacetate (0.088 g, 0.3 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.12 g, 89%).
Reaction SMILES: [OH:1][CH:2]([CH2:9][OH:10])[CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7].[CH2:11]([O:14][CH:15](OCC=C)OCC=C)[CH:12]=[CH2:13].[Cl-].[NH4+]>ClC(Cl)C>[CH2:11]([O:14][CH:15]1[O:1][CH:2]([CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7])[CH2:9][O:10]1)[CH:12]=[CH2:13]
Reactant: O=C(CCl)NCC(O)CO
Reactant: C=CCOC(OCC=C)OCC=C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Product: C=CCOC1OCC(CNC(=O)CCl)O1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
Six and seven-tenths g (0.04 mole) of N-(2,3-dihydroxypropyl)chloroacetamide, 7.3 g (0.04 mole) of triallylorthoformate, 0.2 g of ammonium chloride, and 50 ml of dichloroethane were combined in a reaction flask and distilled to a head temperature of 82° C. The distillate was cooled to room temperature, stirred with potassium carbonate and filtered over Florisil. The filtrate was evaporated to yield 3.2 g of 2-allyloxy-4-(chloroacetylamino)methyl-1,3-dioxolane, a yellow oil. Structure was confirmed by NMR. nD30 =1.4888.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[O:28]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]([F:17])([F:29])[F:30])=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=Nc1ccccc1OC(F)(F)F
Product: COc1ccc(NC(=O)Nc2ccccc2OC(F)(F)F)cc1-c1c(Cl)cnn1C
Yield: 3 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2-trifluoromethoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.5 mg (3%) of Compound 34: LCMS m/z (%)=440 (M+H37Cl, 14), 438 (M+H35Cl, 14). 1H NMR (400 MHz, acetone-d6) δ: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 (d, J=4 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=12 Hz, 2H), 6.99 (dd, J1=8 Hz, H2=2 Hz, 1H), 6.75 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 3.63 (s, 3H), 3.45 (s, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([NH:27][C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[CH3:42])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:45]I.O>CN(C)C=O.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([N:27]([CH3:45])[C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[CH3:42])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)CN2C(=O)c3ccccc3C2=O)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N(C)C(=O)CN2C(=O)c3ccccc3C2=O)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a suspension of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-(phthalimidoacetylamino)benzene (57.4 g) and sodium hydride (4.78 g) in N,N-dimethylformamide (287 ml) was dropwise added methyl iodide (15.5 g) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. Water and ethyl acetate were added thereto, and the resulting precipitate was collected by filtration and washed with water and ethyl acetate to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (28.18 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1)=O>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=3)[N:8]=2)[N:7]=1
Reactant: CCc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)nn1
Solvent: CC#N
Solvent: O
Product: CCc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A solution of 6-chloropyridazin-3-amine (4.76 g, 0.037 mol) and 2-bromo-1-(4-ethyl-3-nitrophenyl)ethanone (10.0 g, 0.037 mol) in acetonitrile (100 mL) is heated at reflux for 18 hr. The reaction mixture is diluted with water (500 mL), stirred at room temperature for 1 hour and solids are collected by filtration to give the title compound (6.9 g, 62% yield). LCMS m/z=303.3, 305.4 [M+H]+, tR=2.90 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.Br[C:29]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[C:35]2[C:30]=1[CH:31]=[CH:32][CH:33]=[N:34]2.C([O-])([O-])=O.[Cs+].[Cs+]>ICCC.COCCOC.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:17]=[C:16]([C:29]3[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:36]=[C:35]4[C:30]=3[CH:31]=[CH:32][CH:33]=[N:34]4)[C:10]3[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=3[CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1)[nH]c(=O)n2C
Reactant: FC(F)(F)c1ccc2ncccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCI
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cc(-c2c(C(F)(F)F)ccc3ncccc23)c2c(c1)[nH]c(=O)n2C
Temperature: 120 °C

Procedure:
To a microwave vial containing 5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (30 mg, 0.08 mmol, 1 equiv.) was added 5-bromo-6-(trifluoromethyl)quinoline (68 mg, 0.24 mmol, 3 equiv.), Cs2CO3 (105 mg, 0.33 mmol, 4 equiv.) and PEPPSI™-IPr catalyst (11 mg, 0.016 mmol, 0.2 equiv.) and dissolved in DME-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 120° C. for 30 min in microwave. The reaction was concentrated in vacuo and purification was then carried out by reverse phase HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11][NH2:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N:13]1[CH:18]=CC=NN=1.[CH2:19](O)C>>[F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:18]=[N:13][CH:19]=[N:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCO
Reactant: NNc1ccc([N+](=O)[O-])c(F)c1
Reactant: c1cnnnc1
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1F
Reaction time: 6 h

Procedure:
The mixture consisting of 2.5 g of 3-fluoro-4-nitrophenylhydrazine, 1.2 g of [1,2,3]triazine and 50 ml of ethanol was heated to reflux with stirring for 6 hours. After concentrating the reaction mixture under reduced pressure, the residue was worked up by column chromatography (solvent: 99:1 dichloromethane:methanol; silica gel).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1>>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([C:21]4[NH:29][C:28]5[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=5[CH:22]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:4]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5cccnc5)nc34)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.3 %

Procedure:
Prepared according to Example 103, using NaH as a 60% dispersion in mineral oil (153 μl, 3.53 mmol, Sigma Aldrich), pyridin-3-ol (335 mg, 3.53 mmol, Sigma Aldrich), and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 150 mg, 0.504 mmol) and stirring at 25° C. for 6 h. Purification by column chromatography (silica gel, 0 to 9% MeOH/DCM) followed by trituration with MeOH provided 2-(2-(3-pyridinyloxy)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (49 mg, 27.3%). 1H NMR (400 MHz, CDCl3) δ ppm 11.07-11.15 (1H, m) 8.72-8.76 (2H, m) 8.68 (1H, d, J=1.00 Hz) 8.26 (1H, d, J=1.00 Hz) 8.04-8.09 (1H, m) 7.61-7.70 (2H, m) 7.45-7.57 (2H, m) 7.09-7.14 (1H, m) 5.38 (1H, br. s) 3.52-3.59 (2H, m) 2.54 (2H, t, J=1.00 Hz). m/z (ESI, +ve) 357.0 (M+H)+.
Reaction SMILES: O.[CH:2]1[C:14]2[CH:13]([C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:26]([NH:28][C:29]3[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:30]=3[C:31]([OH:33])=O)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>CN(C)C=O>[CH:11]1[C:12]2[CH:13]([C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:26]3[O:27][C:31](=[O:33])[C:30]4[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:29]=4[N:28]=3)[CH:23]([CH3:24])[CH3:25])=[O:20])=[O:16])[C:14]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(NC(=O)[C@@H](NC(=O)CNC(=O)C2c3ccccc3-c3ccccc32)C(C)C)c1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2nc([C@@H](NC(=O)CNC(=O)C3c4ccccc4-c4ccccc43)C(C)C)oc(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
33 mg of water-soluble carbodiimide hydrochloride was added under ice-cooling to a solution of 72 mg of 2-[[[N-(9-fluorenylcarbonyl)glycyl]-L-valyl]amino]-6-methylbenzoic acid in 3 ml of N,N-dimethylformamide. The mixture was stirred at 0° C. for 0.5 hour and, then, at room temperature for 18 hours. The mixture was concentrated to give a residue which was purified by a silica gel column chromatography (eluting solution: methylene chlorideether) to afford 60 mg of 2-[1(S)-[[N-(9-fluorenylcarbonyl)glycyl]amino]-2-methylpropyl]-5-methyl-4H-3,1-benzoxazin-4-one as a white powder (see Table 1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]1[CH:17]=[O:18].N(/C(C)(CC)C#N)=N\C(C)(CC)C#N.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C(#N)C>[C:11]1([C:9]2[N:8]=[C:7]([CH:17]=[O:18])[N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][C:10]=23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1nc(-c2ccccc2)cn1CCCCBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCC(C)(C#N)/N=N/C(C)(C#N)CC
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC#N
Product: O=Cc1nc(-c2ccccc2)c2n1CCCC2
Yield: 36.8 %

Procedure:
A solution of 1-(4-bromobutyl)-4-phenyl-1H-imidazole-2-carbaldehyde (918 mg, 3 mmol) in dry acetonitrile (300 mL) was heated at reflux. (E)-2,2′-(Diazene-1,2-diyl)bis(2-methylbutanenitrile) (AIBN) (288 mg, 1.5 mmol) was added followed by addition of tributylstannane (1.93 g, 6.6 mmol) over the course of 2 hours. An additional aliquot of AIBN (288 mg, 1.5 mmol) was added 1 hour after the start of the reaction. The mixture was stirred under reflux for 2 hours. Acetonitrile was removed under reduced pressure. The obtained residue was purified by column chromatography to give 1-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carbaldehyde as a white solid (250 mg). MS (ESI): m/z 227 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:45])[C:7](=[CH2:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:34])[CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24]CC2C=CC=CC=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:33])[CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
860 mg of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide are hydrogenated for 3 hours at room temperature and under normal pressure in the presence of 860 mg of 50% Pd/C in 30 ml of methanol. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by means of FC (100 g of silica gel, dichloro-methane/ethyl acetate=9:1) with separation of the disastereoisomers. The title compound is obtained: Rf (dichloromethane/ethyl acetate=8:2)=0.23.
Reaction SMILES: Br[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[F:15][C:7]1[CH:6]=[C:5]([C@@H:3]2[CH2:2][O:4]2)[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O[C@@H](CBr)c1ccc(C(F)(F)F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Fc1cc([C@@H]2CO2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A mixture of (R)-2-bromo-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanol (3.0 g, 10 mmol), K2CO3 (2.9 g, 21 mmol) and acetone (50 mL) and was stirred for 18 h at RT, then poured in H2O and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with hexane/EtOAc (9:1) to afford 2.0 g (93%) of (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)oxirane (312).