Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([NH:16][CH3:17])=[O:15])=[CH:10][C:5]2=[N:4][CH:3]=1.[N:21]1([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[N:22]1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][CH:20]=[C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([N:21]5[CH:25]=[CH:24][CH:23]=[N:22]5)[CH:31]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[CH:12]=1
Reactant: CNC(=O)c1cccc(-c2ccn3c(Br)cnc3c2)c1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1cccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridine-7-yl)-N-methyl-benzamide (Intermediate EA) (1 eq, 0.303 mmol, 100 mg) and 3-(1H-pyrazolyl)-phenylboronic acid (1.3 eq, 0.394 mmol, 74 mg) are dissolved in DME (3 ml) and water (0.8 ml) and Na2CO3 (3 eq, 0.909 mmol, 96.3 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.015 mmol, 10.6 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-methyl-3-[3-(3-pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-benzamide as a light brown solid; [M+H]+=395
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:5]2[S:10](=[O:11])[CH2:9][CH2:8][C:6]=2[N:7]=1.[N:20]1([C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[C:5]3[S:10](=[O:11])[CH2:9][CH2:8][C:6]=3[N:7]=[C:2]([N:23]3[CH2:22][CH2:21][N:20]([C:26]4[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=4)[CH2:25][CH2:24]3)[N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S1CCc2nc(Cl)nc(Nc3cccc(Cl)c3)c21
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(Nc5cccc(Cl)c5)n3)S(=O)CC4)CC2)cc1
Temperature: 160 °C
Yield: 77.8 %

Procedure:
5.44 g (2-chloro-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-(3-chloro-phenyl)-amine (prepared from 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine and 3-chloroaniline as described in Example 28, see scheme 2), 8.00 g ethyl 4-piperazin-1-yl-benzoate and 4.80 ml diisopropylethylamine are placed in 54 ml dioxane, then heated to 160° C. in the microwave for 0.7 hours. Then the reaction mixture is cooled and mixed with water. The precipitate formed is suction filtered and stirred with petroleum ether/ethyl acetate 1:1, suction filtered and dried. 6.90 g of the product are obtained as a powder.
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:21](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:24])=[CH:28][CH:27]=1
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(CCN)cc1
Product: Cc1ccc(CCNC(=O)[C@H](CCCNC(=O)OC(C)(C)C)N(C)Cc2ccccc2)cc1

Procedure:
Nα-Benzyl-Nδ-Boc-Nα-methylornithine (200 mg) and 2-(4-methylphenyl)ethylamine were coupled to afford the titled compound (108 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.45 (s, 9H), 1.58 (m, 1H), 1.65 (m, 2H), 1.75 (m, 1H), 2.13 (s, 3H), 2.35 (s, 3H), 2.81 (t, J=5.8 Hz, 2H), 3.02 (m, 1H), 3.15 (m, 2H), 3.58 (m, 4H), 7.09 (m, 6H), and 7.27 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccon2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccon2)cc1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
To a solution of 3-(4-methylphenyl)isoxazole (prepared using literature methods) (1.95 g, 12.25 mmol) in carbon tetrachloride (60 mL), N-bromosuccinimide (2.18 g, 12.25 mmol) and benzoyl peroxide (0.059 g, 0.245 mmol) were added and the mixture refluxed for 1 h. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with hexanes/EtOAc to give the title compound, 3-(4-(bromomethyl)phenyl)isoxazole, (0.6 g) as a white solid. 1H NMR (CDCl3): δ 8.48 (d, J=1.6 Hz, 1H), 7.83 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 6.67 (d, J=1.6 Hz, 1H), 4.53 (s, 2H).
Reaction SMILES: CO.[ClH:3].Cl.Cl.[OH:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[NH:17])=[NH:14])=[CH:9][CH:8]=1.[CH3:31][C:32]([CH3:34])=O>>[ClH:3].[CH3:31][C:32]1([CH3:34])[N:14]=[C:13]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:30][CH:29]=2)[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:17]1
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCc1ccc(O)cc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(O)cc2)N1

Procedure:
25 ml of methanol, 40 ml of acetone and 0.1 ml of concentrated hydrochloric acid were added to 1.9 g (4.5 mmol) of N1-(4-hydroxybenzyl)-N5-decyl-biguanide dihydrochloride, and the mixture was refluxed for 30 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized with 80% aqueous acetonitrile to obtain 0.4 g of colorless crystals having a melting point of 109 to 111° C.
Reaction SMILES: OS([C:5]([F:8])(F)F)(=O)=O.[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][CH2:20][C@H:21]2[CH2:25][CH2:24]C([Sn](C)(C)C)=[C:22]2[C:30]2[CH:35]=[CH:34][C:33]([CH:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][CH:31]=2)=[CH:16][CH:17]=1)=[O:12].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl.[Al]>[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][CH2:20][C@H:21]2[CH2:25][CH2:24][C:5]([F:8])=[C:22]2[C:30]2[CH:31]=[CH:32][C:33]([CH:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:34][CH:35]=2)=[CH:16][CH:17]=1)=[O:12]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C([Sn](C)(C)C)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: [Al]
Solvent: ClCCl
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(F)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 0.5 h
Yield: 5 %

Procedure:
An analogous procedure to that described in Marcus A. Tius and Joel K. Kawakami Tetrahedron 1995, 51, 3997 was used. A solution of triflic acid (37 μL, 0.42 mmol) in 0.37 mL CH2Cl2 was added to a mixture of Ag2CO3 (83 mg, 0.30 mmol) in 2.8 mL CH2Cl2 and the flask was covered in aluminum foil. After 30 min., a solution of 57 (ca. 0.38 mmol, directly from above) and 2,6-di-tert-butyl-4-methylpyridine (49 mg, 0.24 mmol) in 2.8 mL CH2Cl2 was added dropwise by cannula, rinsing with 1 mL CH2Cl2. At this time, a solution of XeF2 (82 mg, 0.48 mmol) in 5.5 mL CH2Cl2 was added by cannula. The reaction was stirred for 1 h and then was quenched by addition of 10 mL saturated NaHCO3 solution. The resulting mixture was extracted with CH2Cl2 (3×30 mL) and the combined solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on a Teledyne Isco Combiflash unit (40 g silica gel column, 0%→100% ethyl acetate/hexanes) followed by HPLC (Phenomenex 50 mm×250 mm silica gel column, 5% ethyl acetate/hexanes) to give the title compound (12 mg, 5%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([CH2:13][C:14](OCC)=[O:15])#[N:12]>CN(C)C=O.C(OCC)(=O)C>[C:11]([CH2:13][C:14]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:15])#[N:12]
Reactant: CCOC(=O)CC#N
Reactant: NCCc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCC(=O)NCCc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
1.28 g (9.33 mmol) of tyramine is added to a solution containing 1.00 g (8.84 mmol) of ethyl cyanoacetate in 13 mL of dimethylformamide under an inert atmosphere. The mixture is stirred at 110° C. for 4 hours, then at room temperature for 12 h. The reaction medium is then diluted in 100 mL of ethyl acetate and washed with 50 mL of an aqueous acid solution at pH=3. The aqueous phase is again extracted with 50 mL of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and the solvent is evaporated under reduced pressure. The resulting viscous brown solid is then dissolved several times in toluene and the toluene azeotrope/DMF is evaporated. Finally, the solid is washed with dichloromethane and ether. The product is isolated in the form of a pale brown solid with a yield of 65%.
Reaction SMILES: [C:1]12([CH2:11]O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)C1)[CH2:8]2.[CH3:13][C:14]1([CH3:26])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)[O:15]1.CC1C(B2OC(C)(C)C(C)(C)[O:34]2)=C(C)NN=1>>[C:1]12([CH2:11][N:24]3[CH:25]=[C:21]([B:16]4[O:17][C:18]([CH3:19])([CH3:20])[C:14]([CH3:26])([CH3:13])[O:15]4)[CH:22]=[N:23]3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[O:34]1)[CH2:10]2
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC1(C)OB(c2cnn(CC34CC5CC(CC(C5)O3)C4)c2)OC1(C)C

Procedure:
The title compound was prepared by substituting EXAMPLE 13A for 1-adamantanemethanol and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 2A.
Reaction SMILES: [CH:1]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.O=[O+][O-]>>[CH:1]1=[CH:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C1=CCCCCCCC=C1
Agent: C1=CCCCC/C=C/CC1
Agent: O=[O+][O-]
Product: C1=CCCCCC=CCC1

Procedure:
The example No. I-2 is repeated (using cyclodecadiene (CDD) as cycloolefin). In this case as well, a 1 : 1 reaction between olefin and ozone is found.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[C:5]([C:12]([OH:14])=O)=[CH:6][NH:7]2.[CH:16]12[N:22]([C:23]3[N:28]=[CH:27][C:26]([NH2:29])=[C:25]([CH3:30])[CH:24]=3)[CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:16]12[N:22]([C:23]3[N:28]=[CH:27][C:26]([NH:29][C:12]([C:5]4[C:4](=[O:15])[C:3]5[C:8](=[CH:9][CH:10]=[CH:11][C:2]=5[CH3:1])[NH:7][CH:6]=4)=[O:14])=[C:25]([CH3:30])[CH:24]=3)[CH:19]([CH2:20][CH2:21]1)[CH2:18][CH2:17]2
Reactant: Cc1cc(N2C3CCC2CC3)ncc1N
Reactant: Cc1cccc2[nH]cc(C(=O)O)c(=O)c12
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: Cc1cc(N2C3CCC2CC3)ncc1NC(=O)c1c[nH]c2cccc(C)c2c1=O
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a solution of 5-methyl-4-oxo-1H-quinoline-3-carboxylic acid (60 mg, 0.2953 mmol) and 6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-methyl-pyridin-3-amine (60.03 mg, 0.2953 mmol) in 2-methyltetrahydrofuran (1 mL) was added propyl phosphonic acid cyclic anhydride (375.8 μL of 50% w/v, 0.5906 mmol) followed by pyridine (46.72 mg, 47.77 μL, 0.5906 mmol). The mixture was irradiated under microwave conditions for 1 h at 100° C. The crude reaction mixture was diluted with ethyl acetate (2 mL) and quenched with 10% NaHCO3 solution (3 mL). The resulting precipitate was filtered and washed with ethyl acetate (5 mL). The solid was resuspended in 20% aqueous Na2CO3 (5 mL)/methanol (2 mL) and stirred for 30 min. The solid was filtered, rinsed with water and air dried to provide N-(6-(7-azabicyclo[2.2.1]heptan-7-yl)-4-methylpyridin-3-yl)-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (30 mg, 26% yield). LC/MS m/z 389.4 [M+H]+, retention time 1.33 min (RP—C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH3:21])[CH2:15][C@H:14]1[C@@H:13]([CH3:22])[S:12][C:11]([NH:23]C(=O)C1C=CC=CC=1)=[N:10]2.FC1C=C(F)C=CC=1[C@]12CO[C@@H](CF)C[C@H]1[C@@H](C)SC(NC(=O)C1C=CC=CC=1)=N2.FC1C=C(F)C=CC=1[C@]12CO[C@@H](CF)C[C@H]1[C@@H](C)SC(N)=N2.CO>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH3:21])[CH2:15][C@H:14]1[C@@H:13]([CH3:22])[S:12][C:11]([NH2:23])=[N:10]2
Reactant: COC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: C[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Agent: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Solvent: CO
Solvent: ClCCl
Product: COC[C@H]1C[C@H]2[C@@H](C)SC(N)=N[C@@]2(c2ccc(F)cc2F)CO1

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C20) was deprotected using the method described for conversion of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C19) to (4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (1) in Example 1. In this case, the chromatography was carried out using a gradient of 0% to 10% methanol in dichloromethane; the product was isolated as a white solid. Yield: 69.3 mg, 0.202 mmol, 83%. LCMS m/z 343.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.32 (ddd, J=9.6, 9.0, 6.6 Hz, 1H), 6.92-7.00 (m, 2H), 4.10 (dd, J=11.1, 2.2 Hz, 1H), 3.75-3.82 (m, 1H), 3.72 (d, J=11.1 Hz, 1H), 3.47 (dd, half of ABX pattern, J=10.3, 6.4 Hz, 1H), 3.41 (dd, half of ABX pattern, J=10.3, 3.9 Hz, 1H), 3.38 (s, 3H), 3.05-3.13 (m, 1H), 2.71-2.78 (m, 1H), 1.55-1.62 (m, 1H), 1.36-1.47 (m, 1H), 1.17 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[CH2:23]=[O:24].[K+].[Br-].[NH2:27][C:28]1[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=1)/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCCl>[C:10]([O:9][C:7]([CH:6]1[CH2:14][CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]1[C:3](=[O:4])[CH2:2][NH:1][C:23](=[O:24])[NH:27][C:28]1[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=1)/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: C=O
Reactant: CCOC(=O)/C=C/c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CN
Agent: [Br-]
Agent: [K+]
Solvent: ClCCCl
Product: CCOC(=O)/C=C/c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1

Procedure:
By proceeding in a fashion similar to that described in Example 3, but starting from 3.6 g of N,N'-carbonyldiimidazole, 6.2 g of tert-butyl (2RS,5SR)-1-(2-aminoacetyl)-5-phenylprolinate in solution in 150 cm3 of anhydrous 1,2-dichloroethane and 3.9 g of ethyl (E)-3-aminocinnamate, 4.8 g of ethyl (E)-3-{3-[2-((2RS,5SR)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}cinnamate are obtained [proton NMR (250 MHz, DMSO D6, δ in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 120° C.: 1.3 (t, 3H, CH3); 1.5 (bs, 9H, (CH3)3); 4.25 (q, 2H, CH2O); 6.4 (d, 1H, J=15, CH= trans); 7.10 to 7.70 (m, 10H, aromatic and CH= trans). Infrared spectrum (KBr), characteristic bands in cm-1 : 3375, 3150, 3070, 3035, 2980, 2940, 2880, 1740, 1700, 1640, 1610, 1590, 1560, 1495, 1490, 1455, 1430, 1395, 1370, 1310, 1270, 1220, 1180, 1160, 1040, 990, 860, 840, 790, 760, 705, 685].
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][C:19](=[O:21])[CH2:18][C@@H:17]1[C@H:22]1[O:26][C:25]([CH3:28])([CH3:27])[N:24]([C:29](=[O:31])[CH3:30])[C@H:23]1[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CCOCC.C(OCC)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:20][C@@:19]([OH:21])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:18][C@@H:17]1[C@H:22]1[O:26][C:25]([CH3:27])([CH3:28])[N:24]([C:29](=[O:31])[CH3:30])[C@H:23]1[CH2:32][C:33]1[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([F:39])[CH:38]=1)=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(=O)CN2C(=O)OC(C)(C)C)OC1(C)C
Reactant: Br[Mg]c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@](O)(c3ccccc3)CN2C(=O)OC(C)(C)C)OC1(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
Add phenyl magnesium bromide (3.0 mL, 9 mmol, 3M in ether) dropwise to an ice cold solution of (R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (0.40 g, 0.89 mmol) in ether (20 mL). Stir 60 minutes and warm to 23° C. Dilute with ethyl acetate and wash with saturated aqueous ammonium chloride. Purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound as a foam (0.19 g, 41%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[C:32]([CH3:31])=[N:33][NH:34][CH:35]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1n[nH]cc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), 3-methyl-1H-pyrazole-4-boronic acid pinacol ester (135 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=30:70) to obtain the title compound (213 mg, 71%) in an orange oily form.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O.C(=O)(O)[O-].[Na+].O>[N:23]([CH2:21][CH:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 1,4-dibenzyl-2-chloromethyl-piperazine (8.8 g, 0.028 mol) in dimethylformamide (90 mL) under nitrogen was added sodium azide (5.5 g) and the reaction stirred at 50° C. for 18 h. The reaction was cooled and diluted with 10% aqueous sodium bicarbonate (100 mL) and water (250 mL) and the mixture extracted with ethyl acetate (2×200 mL). The organic extracts were washed with 10% sodium bicarbonate, brine, dried over sodium sulfate and concentrated to an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:21])[NH:19][OH:20])[CH:8]=[CH:9]2)[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].CS(C)=O.[CH3:31][N:32]=[C:33]=[O:34]>O>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:21])[NH:19][O:20][C:33]([NH:32][CH3:31])=[O:34])[CH:8]=[CH:9]2)[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CN=C=O
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1c2ccc(CC(=O)NOC(=O)NC)ccc-2c(C(=O)OCC)c1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.2 g (0.55 mmol) of diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate, 5 ml of dimethyl sulphoxide and 35 □l (0.6 mmol) of methyl isocyanate is stirred at room temperature for 18 hours. Thereafter, the mixture is diluted with water, extracted with dichloromethane and the extract is chromatographed on silica gel. Elution with ethyl acetate gives 60 mg (36% of theory) of the title compound of m.p. 222-224° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O1CCCC1.C(Cl)Cl>[N:16]1([CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=2[F:1])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc(Br)cc1COCCCCN1CCOCC1
Reaction time: 72 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (550 mg, 1.62 mmol) in tetrahydrofuran (8 ml) was treated with morpholine (1.4 ml, 16.2 mmol). The resulting reaction mixture was stirred for about 72 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: CC(C)(C(=O)NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(Cl)cc1

Procedure:
Example 115 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.94–7.81 (br, 1H), 7.53–7.40 (br, 1H), 7.39–7.15 (m, 6H), 6.82 (d, 1H, J=7.2 Hz), 6.68–6.49 (br, 1H), 3.33–3.19 (m, 2H), 3.19–3.06 (m, 2H), 2.63–2.39 (m, 3H), 2.31–2.09 (m, 2H), 1.89–1.62 (m, 7H), 1.54 (s, 6H), 1.13–0.98 (m, 2H), 0.90–0.72 (m, 2H); ESMS m/e: 482.2 (M+H)+.