Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][C@@H:8]([CH2:14][C:15]([O:17]C(C)(C)C)=O)[C:7](=[O:22])[O:6][CH2:5][C@@H:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:3]1.FC(F)(F)C(O)=O.O=C1CCC=CC[C@@H](CC(O)=O)C(=O)OC[C@@H](C2C=CC=CC=2)N1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:74][C:75]1[CH:82]=[CH:81][C:78]([CH2:79][NH2:80])=[CH:77][CH:76]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:74][C:75]1[CH:82]=[CH:81][C:78]([CH2:79][NH:80][C:15](=[O:17])[CH2:14][C@H:8]2[C:7](=[O:22])[O:6][CH2:5][C@@H:4]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:3][C:2](=[O:1])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]2)=[CH:77][CH:76]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C[C@@H]1CC=CCCC(=O)N[C@H](c2ccccc2)COC1=O
Agent: CC(C)(C)OC(=O)C[C@@H]1C/C=C/CCC(=O)N[C@H](c2ccccc2)COC1=O
Agent: CN(C)c1ccncc1
Agent: O=C(C[C@@H]1C/C=C/CCC(=O)N[C@H](c2ccccc2)COC1=O)NCc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C[C@@H]1CC=CCCC(=O)N[C@H](c2ccccc2)COC1=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-((3R,11S,E)-5,12-dioxo-3-phenyl-1-oxa-4-azacyclododec-8-en-11-yl)acetate (130 mg, 0.336 mmol) in CH2Cl2 (258 μL) cooled in an ice/water bath was added trifluoroacetic acid (116 μL, 1.510 mmol) and the reaction mixture was stirred 1 h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was concentrated and the crude carboxylic acid was utilized immediately. To a solution of crude 2-((3R,11S,E)-5,12-dioxo-3-phenyl-1-oxa-4-azacyclododec-8-en-11-yl)acetic acid (111 mg, 0.335 mmol) in CH2Cl2 (4.2 mL) cooled in an ice/water bath was added EDC (64.2 mg, 0.335 mmol) and HOBt (45.3 mg, 0.335 mmol) and the resulting solution was stirred 30 min 4-chlorobenzylamine (41.0 μL, 0.335 mmol), iPr2NEt (176 μL, 1.005 mmol) and DMAP (4.09 mg, 0.033 mmol) were subsequently added and the reaction mixture was slowly warmed to rt and stirred for 16 h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was diluted with saturated NH4Cl and EtOAc and the layers separated. The aqueous was extracted 2× with EtOAc and the combined organic extracts were washed with 1 N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield the desired product as a white solid. 1H NMR (300 MHz, (CD3)2SO): δ 1.95-2.57 (m, 7H), 2.73-2.80 (m, 1H), 3.65 (dd, 1H, J=3.6, 11.3), 4.20 (s, 1H), 4.22 (s, 1H), 4.61 (apparent triplet, 1H, J=11.3), 5.23-5.34 (m, 3H), 7.22-7.24 (m, 9H), 8.25 (d, 1H, J=9.5), 8.41-8.46 (m, 1H); LRMS (M+H)+: 455.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[C:5]([F:17])=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[C:5]=1[F:17]
Reactant: O=C1NCCCn2c1cc1c(F)c(F)cc(Br)c12
Reactant: OB(O)c1ccc(F)cc1
Product: O=C1NCCCn2c1cc1c(F)c(F)cc(-c3ccc(F)cc3)c12

Procedure:
The title compound, light grey solid (79 mg, 96%), MS (ISP) m/z=331.2 [(M+H)+], mp 287° C., was prepared in accordance with the general method of example 1 from 7-bromo-9,10-difluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 5) (78.8 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=O)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>C1COCC1>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C@H:22]3[CH2:23][CH2:24][C@H:25]([CH2:28][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH2:26][CH2:27]3)=[CH:19][CH:20]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N[C@H]2CC[C@H](C(=O)N3CCN(C)CC3)CC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N[C@H]2CC[C@H](CN3CCN(C)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Compound 107t (0.0572 g, 0.117 mmol) was dissolved in THF (1.1 mL), and a solution of lithium aluminum hydride (0.0178 g, 0.468 mmol) and aluminum chloride (0.0312 g, 0.234 mmol) in THF (3.0 mL) was added to the solution, followed by stirring at 0° C. for 15 minutes. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution, and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to obtain Compound 108t (0.0426 g, 0.0897 mmol, yield 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[C:5]([NH:7][CH2:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10])=[O:6]>CCOC(C)=O.[Pd]>[NH2:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(F)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)NCC(=O)O)cc1F
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
To a solution of benzyl 2-(3-fluoro-4-nitrobenzamido)acetate (200 mg) in EtOAc (10 mL) was added Pd/C (10%, 200 mg) at rt and stirred under the atmosphere of H2 gas for 20 min. Work-up of the reaction mixture as described in example 1 gave product as an off-brown color solid (100 mg, 79%), mp 198-200° C. 1H NMR (400 MHz, DMSO-d6): δ 12.52 (1H, br s), 8.45 (1H, br s), 7.52 (1H, d, J=13.2 Hz), 7.47 (1H, d, J=8.0 Hz), 6.77 (1H, t, J=8.4 Hz), 5.71 (2H, s), 3.87 (2H, d, J=5.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ 171.5, 165.5, 149.5 (d, J=235 Hz), 139.7 (d, J=13.0 Hz), 124.3 (d, J=2.0 Hz), 121.1 (d, J=6.0 Hz), 114.8 (d, J=4.0 Hz), 114.0 (d, J=20.0 Hz), 41.2; LC-MS (negative ion mode): m/z 211 (M−H)−.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:3][C:4]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=2[CH:6]=[O:7])=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
Sodium hydride (0.66 g) was added in portions to a stirred solution of 3.90 g of 2-hydroxy-4-methoxybenzaldehyde in N,N'-dimethylformamide (70 mL) under nitrogen. To the resulting milky, green mixture was added 1,4-dichloro-2-nitrobenzene (4.47 g). The reaction was placed in an oil bath and stirred at 90° C. for 16 hours. The reaction Was then evaporated and the residue partitioned between chloroform (75 mL) and 1N NaOH (50 mL). The layers were separated and the aqueous layer Was extracted with chloroform (75 mL). The chloroform extracts were combined and washed With Water (75 mL) and brine (75 mL), dried over magnesium sulfate, and evaporated in vacuo. The orange solid was recrystallized from ethyl acetate/iso-propyl ether to yield 3.86 g (53.9%) of product as light yellow, shiny crystals.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.B.O1CCCC1.O.C(OCC)(=O)C>O1CCCC1>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1cc(I)ccc1O
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1cc(I)ccc1O
Yield: 0.8 %

Procedure:
To a solution of 5-iodosalicylic acid (1 g, 0.378 mol) in anhydrous tetrahydrofuran (4 ml) at 0° C. was added dropwise borane-tetrahydrofuran complex (1.0M solution in tetrahydrofuran, 11.4 ml). After fifteen minutes at room temperature, the mixture was heated at reflux for two hours. Water and ethyl acetate were added to the cooled solution, the organic phase separated and evaporated to give crude product. The residue was washed with pentane to afford 0.8 g (84.21%) of 2-hydroxy-5-iodo-benzyl alcohol, m.p. 125° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.[Br-]>CN(C=O)C.O>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:29][CH:28]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)OCC
Temperature: 0 °C
Yield: 84.8 %

Procedure:
60% mineral oil suspension of sodium hydride (1.454 g; 36.3 mmol) was added into anhydrous DMF (50 mL) under nitrogen at 0° C. Diethyl malonate (5.82 g; 36.3 mmol) was added to the stirred suspension over 10 min and the mixture was then stirred rapidly at 0° C. until a clear pale yellow solution was obtained. 4-(bromomethyl)benzophenone (5.00 g; 18.2 mmol) in DMF (15 mL) was added dropwise over 5 min and the reaction mixture was stirred for 16 h at ambient temperature. Complete conversion of the starting bromide was confirmed by TLC. The reaction was diluted with water (400 mL) and extracted with dichloromethane (3×50 mL). The organic phase was separated, dried and evaporated to an oily residue. Chromatography on silicagel (eluent hexane/2-butanone 10:1→5:1) provided the desired 1,3-diethyl 2-[(4-benzoylphenyl)methyl]propanedioate (5.47 g; 86%) as a colourless oil.
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>N1C=CC=CC=1>[C:2]1([CH2:1][S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)Cc1ccccc1
Yield: 63.1 %

Procedure:
Prepared according to the procedure described for Example 121 using benzylsulfonyl chloride (1.90 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (2.5 g); m.p. 216-216° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:30](=[O:31])[C:29]([CH3:34])([CH3:33])[CH3:28])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)C(C)(C)C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and 2,2-dimethylpropanoyl chloride (18 mg, 150 μmol). Yield 17 mg (74%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]=[O:9]
Reactant: Cc1cccc(C)c1O
Reactant: O=CN1CCC[C@H]1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OC[C@@H]1CCCN1C=O
Reaction time: 0.17 h

Procedure:
A mixture of (3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-((S)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanone (2.0 g; 7.7 mmol), which was prepared as described in example P8, triphenylphosphine (2.1 g; 8.0 mmol) and 2,6-dimethylphenol (0.94 g; 7.7 mmol) in dry THF (30 ml) was cooled in an ice-bath. Diisopropyl azocarboxylate (1.60 g; 8.0 mmol) in dry THF (15 ml) was added dropwise, with stirring under nitrogen atmosphere over 10 minutes. The reaction mixture was stirred at ambient temperature for 6 hours. After removal of the solvent in vacuo, the residue (6.81 g) was purified by flash chromatography using silica gel (eluent: cyclo hexane/ethyl acetate 2:8). 1.31 g (46.8% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-[(S)-2-(2,6-dimethyl-phenoxymethyl)-pyrrolidin-1-yl]-methanone (compound 1.225) was obtained in form of a white solid m.p. 137-140° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]([CH3:32])[CH3:31])[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]([CH3:32])[CH3:31])[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC(C)C)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OC(C)C)c23)c1
Yield: 64.4 %

Procedure:
Using an analogous procedure to that described in Example 20, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-isopropoxyquinazoline (0.33 g) was reacted with trifluoroacetic acid. There was thus obtained the title compound (0.17 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.55 (d, 6H, 3.85 (s, 3H), 5.1 (m, 1H), 6.8 (s, 1H), 6.92 (s, 1H), 7.0 (m, 1H), 7.58 (d, 1H), 7.65 (d, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 360 and 362.
Reaction SMILES: O1CCNC1=O.[NH2:7][CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([N:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:23]3=[O:48])=[C:17]([CH3:49])[CH:16]=2)[CH2:10]1.[Cl:50][C:51]1[S:55][C:54]([C:56](Cl)=[O:57])=[CH:53][CH:52]=1>>[C:44]([Si:31]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[O:30][CH2:29][CH2:28][C:24]1[C:23](=[O:48])[N:22]([C:18]2[C:17]([CH3:49])=[CH:16][C:15]([N:11]3[CH2:10][C@H:9]([CH2:8][NH:7][C:56]([C:54]4[S:55][C:51]([Cl:50])=[CH:52][CH:53]=4)=[O:57])[O:13][C:12]3=[O:14])=[CH:20][C:19]=2[CH3:21])[CH:27]=[CH:26][CH:25]=1)([CH3:45])([CH3:46])[CH3:47]
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: Cc1cc(N2C[C@H](CN)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: O=C1NCCO1
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
To prepare the compound of the Formula (Ia), 3-bromopyridin-2(1H)-one (III) is reacted with 1-fluoro-2,5-dimethyl-4-nitrobenzene (IV) to give 3-bromo-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (V). Then, (V) is converted with tributylvinyl tin and tetrakis(triphenylphosphine)palladium into 1-(2,6-dimethyl-4-nitrophenyl)-3-vinylpyridin-2(1H)-one (VI). Hydroboration and oxidation of (VI) produces 1-(2,6-dimethyl-4-nitrophenyl)-3-(2-hydroxyethyl)pyridin-2(1H)-one (VII). In order to protect the hydroxy group, (VII) is reacted with tert-butyl(chloro)diphenylsilane in the presence of a base, giving 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (VIII). The reduction of the nitro group in (VIII) leads to 1-(4-amino-2,6-dimethylphenyl)-3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (IX). Then follows the reaction of (IX) with (S)-epoxyphthalimide (X) to give 2-[(2R)-3-({4-[3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}amino)-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione (XI). Ring closure to the oxazolidinone and cleaving off the phthalimide group produces starting from (XI) 1-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,6-dimethylphenyl}-3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (XII), which is reacted with 5-chlorothiophene-2-carbonyl chloride (XIII) to give N-[((5S)-3-{4-[3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chlorothiophene-2-carboxamide (XIV). Cleaving off the protective group in (XIV) produces 5-chloro-N-[((5S)-3-{4-[3-(2-hydroxyethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]thiophene-2-carboxamide (IIa), which is reacted with trans-4-aminohexanol (XV) to give 5-chloro-N-{[(5S)-3-{4-[3-{2-[(trans-4-hydroxycyclohexyl)amino]ethyl}-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl}thiophene-2-carboxamide (Ia).
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:48]1[CH:49]=[C:50]([C:55]#[N:56])[CH:51]=[C:52]([F:54])[CH:53]=1.C1(C)C=CC=CC=1.[CH2:64]([O:66]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:65]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:64]([C:48]1[CH:49]=[C:50]([C:55]#[N:56])[CH:51]=[C:52]([F:54])[CH:53]=1)(=[O:66])[CH3:65]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(F)cc(C#N)c1

Procedure:
Under an argon atmosphere, 824 mg (0.900 mmol) of tris(dibenzylideneacetone)dipalladium and 1.23 g (1.98 mmol) of rac-1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) are added to 9.00 g (45.0 mmol) of 3-bromo-5-fluorobenzenecarbonitrile in toluene (300 mol). After the addition of 19.5 g (54.0 mmol) of (1-ethoxyvinyl)tributylstannane, the mixture is stirred under reflux overnight. The reaction mixture is subsequently concentrated and the residue is taken up in 300 ml of THF. After the addition of 100 ml of an aqueous 2N hydrogen chloride solution, the mixture is stirred at room temperature for 2 h. The reaction mixture is subsequently neutralized using a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 9:1). 7.11 g (97% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:15][CH2:16][CH:17]([OH:24])[C:18]2[N:19]=[C:20]([Cl:23])[S:21][CH:22]=2)[CH3:14])=[CH:8][CH:7]=1)(O)=[O:2].B.O1CCCC1>>[OH:2][CH2:1][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:15][CH2:16][CH:17]([OH:24])[C:18]2[N:19]=[C:20]([Cl:23])[S:21][CH:22]=2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CC(Cc1ccc(OCC(=O)O)cc1)NCC(O)c1csc(Cl)n1
Agent: B
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCCO)cc1)NCC(O)c1csc(Cl)n1

Procedure:
Prepared by analogy to Example 71 by reaction of N-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-chlorothiazol-4-yl)ethanamine with borane/tetrahydrofuran complex (1 molar solution in tetrahydrofuran) for 24 hours.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+]>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
2-Fluoro-5-nitroaniline (15.7 g) solution in pyridine (100 ml) was added drop-wise with methanesulfonylchloride (17.2 g) in an ice bathing. After being stirred for 2 hours at room temperature, the reaction mixture was added with 2N sodium hydroxide (200 ml) and washed with hexane (200 ml) two times. 2N HCl (300 ml) was added into the resultant aqueous layer and solids separated were collected by filtration, washed with water and dried under vacuum to obtain 2′-fluoro-5′-nitromethanesulfonanilide (21.8 g) as brownish solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.[NH2:28][C:29](N)=[NH:30].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)[C:29]([NH2:30])=[NH:28]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: N=C(N)N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=N)N)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.43 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (30 mg, 81.87 μmol), 1,3-di-boc-2-trifluoromethylsulfonyl)guanidine (38.45 mg, 98.25 μmol) and triethylamine (22.82 μL, 163.7 μmol) in DCM was stirred at room temperature for 5 hours. Then to the mixture was added TFA (6.308 μL, 81.87 μmol) and the mixture was stirred overnight. The crude product was purified by column chromatography to afford the title compound as brown oil in 49.43% yield. LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 3.5 (t, J=5.1 Hz, 2H) 3.7 (s, 3H) 3.9 (s, 3H) 4.1 (t, J=5.1 Hz, 2H) 6.3 (d, J=2.0 Hz, 1H) 7.1 (d, J=5.6 Hz, 1H) 7.2 (d, J=9.1 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.5 (d, J=2.0 Hz, 1H) 7.6 (d, J=3.0 Hz, 1H) 7.8 (dd, J=8.8, 2.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]=[N:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=NCc2ccccc2)CC1
Reaction time: 120 h

Procedure:
A mixture of (4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester (3.80 g, 16.7 mmol), benzylamine (1.82 g, 16.7 mmol), acetic acid (0.01 g, 16.7 mmol) and anhydrous magnesium sulfate (4.01 g, 33.3 mmol) in methylene chloride (20 mL) was stirred for 5 days. The mixture was filtered through Celite and concentrated under reduced pressure to give trans-[4-(benzylimino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.10 g, 97%) as a 97:3 trans:cis mixture.