Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:30][C:12]2=[CH:13][C:14]3[C:15](=[O:29])[N:16]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([CH2:38][CH:39]([NH2:41])[CH3:40])[CH:37]=1.CCN(C(C)C)C(C)C>C(O)CCC>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([CH2:38][CH:39]([NH:41][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:30][C:12]3=[CH:13][C:14]4[C:15](=[O:29])[N:16]([CH:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[C:17](=[O:21])[C:18]=4[C:19]([CH3:20])=[C:11]3[N:10]=2)[CH3:40])[CH:37]=1
Reactant: Cc1ccc(F)cc1CC(C)N
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Yield: 100.1 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.35 mmol), 1-(5-fluoro-2-methylphenyl)propan-2-amine (0.47 g, 2.82 mmol), Hunig's base (1.52 g, 0.011 mol), and 20 mL of anhydrous 1-butanol was heated at reflux for 14-15 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 1.31 g (99%) of the designed compound as yellowish solid. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (s, 1H, NH), 11.25 (d, J=6.3 Hz, 1H, NH), 11.02 (d, J=8.1 Hz, 1H, NH), 7.98 (s, 1H, ArH), 7.32 (t, J=7.2 Hz, 1H, ArH), 7.16-7.07 (m, 2H, ArH), 6.92-6.86 (m, 1H, ArH), 6.17 (d, J=7.5 Hz, 1H, ArH), 4.34-4.19 (m, 2H, 2×CH), 3.51-3.47 (m, 2H, CH2), 3.18-3.11 (m, 2H, CH2), 2.97 (d, J=6.3 Hz, 2H, CH2), 2.83 (s, 3H, CH3), 2.76 (s, 31-1, CH3), 2.69-2.61 (m, 2H, CH2), 2.27 (s, 3H, CH3), 1.95-1.91 (m, 2H, CH2), 1.34 (d, J=6.3 Hz, 3H, CH3); Mass (ESI, positive) m/z 557.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.ON1C2C=CC=CC=2N=N1.[C:47]([O:51][C:52](=[O:61])[NH:53][C:54]([CH3:60])([CH2:57][CH2:58][CH3:59])[CH2:55][NH2:56])([CH3:50])([CH3:49])[CH3:48].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:47]([O:51][C:52](=[O:61])[NH:53][C:54]([CH3:60])([CH2:57][CH2:58][CH3:59])[CH2:55][NH:56][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:2]=3[F:1])=[CH:7][C:8]([CH3:19])=[CH:9][C:10]=12)=[O:17])([CH3:50])([CH3:49])[CH3:48]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: Cc1cc(OCc2cccc(F)c2F)n2nc(C)c(C(=O)O)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3cccc(F)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 120 mg (0.336 mmol) of 7-[(2,3-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 117A in 2 ml of DMF was admixed with 70.8 mg (0.437 mmol) of 1,1′-carbonyldiimidazole and 36 mg (0.235 mmol) of 1-hydroxybenzotriazole. After stirring at room temperature for 15 min, 94.4 mg (0.437 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A were added, followed by 0.117 ml (0.672 mmol) of N,N-diisopropylethylamine. The tubes were sealed and introduced into a Biotage Initiator with microwave irradiation at 100° C. for 20 minutes. The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml), the phases were separated and the aqueous phase was acidified to pH=5 with 2 N aqueous hydrochloric acid and extracted with dichloromethane (2×15 ml). The combined organic phases were concentrated under reduced pressure and the residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 35 mg (15% of theory, 78% pure) of the target compound.
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[C:13](=[N:16]O)[CH:12]2[CH2:18][CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:19].[H][H]>[Pd].C(O)C>[ClH:19].[NH2:16][CH:13]1[CH:12]2[CH2:18][CH:9]([CH2:10][CH2:11]2)[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:14]1=[O:15]
Reactant: O=C1C(=NO)C2CCC(C2)C1Cc1ccccn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC1C(=O)C(Cc2ccccn2)C2CCC1C2
Reaction time: 3 h
Yield: 86 %

Procedure:
A solution of 2-aza-2-benzyl-4-oximino-3-oxo-bicyclo[3,2,1]octane in 10 mL/mmole of ethanol and 5.8 mL/mmole of 3N HCl containing 0.5 g/mmole of 10% Pd/C was saturated with hydrogen gas to 45 psi. The mixture was shaken for 3 hours and then filtered through a layer of Celite. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as a solid (86% yield). This procedure is further described in E. Reimann, Arch. Pharm. 310, 102-109 (1977).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([OH:28])[C@@:17]([OH:27])([C:23]([O:25]C)=[O:24])[CH2:18][C:19]([O:21]C)=[O:20]>Cl.O>[C:23]([C@:17]([OH:27])([C@@H:16]([OH:28])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:18][C:19]([OH:21])=[O:20])([OH:25])=[O:24]
Reactant: COC(=O)C[C@](O)(C(=O)OC)[C@@H](O)CCCCCCCc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Product: O=C(O)C[C@](O)(C(=O)O)[C@@H](O)CCCCCCCc1ccc(Cl)cc1Cl
Yield: 68 %

Procedure:
±(3R*,4S*) Methyl 11-(2,4-dichlorophenyl)-3,4-dihydroxy-3-methoxycarbonylundecanoate (189 mg, 0.434 mmol: prepared in analogous fashion to the higher homologue described in example 5) was heated under reflux in aqueous HCl (7.7M) for 3 h. The solution was cooled, diluted with water, and extracted with ether. The extracts were washed with aqueous NaOH, then the aqueous phase washed with ether, and acidified (aqueous HCl). The mixture was extracted with ether again. The extracts were washed with water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under vacuum, and the residue recrystallised (ether/petroleum ether 40°-60° C.) to give the title compound (115 mg, 68%) as a white solid, m.p. 104°-105° C.
Reaction SMILES: [C:1]1([CH3:15])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[S:16]1[CH2:22][C:20](=[O:21])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:17]1=[S:18].[Cl-].[NH4+].N>C(O)C>[C:1]1([CH3:15])[C:2]([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=[C:22]3[S:16][C:17](=[S:18])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:20]3=[O:21])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1Nc1nc(C=O)cs1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccccc1Nc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.12 g of 2-(o-toluidino)thiazole-4-carbaldehyde, 0.87 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 15 ml of ethanol. The resulting product was an orange powder having the following physical properties.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:27]2[C:31]3=[N:32][C:33]([CH3:37])=[CH:34][C:35]([CH3:36])=[C:30]3[C:29]([C:38]#[N:39])=[CH:28]2)=[CH:22][CH:21]=1.CN(C)[CH:48]=[O:49]>O1CCCC1.O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:27]2[C:31]3=[N:32][C:33]([CH3:37])=[CH:34][C:35]([CH3:36])=[C:30]3[C:29]([C:38]#[N:39])=[C:28]2[CH:48]=[O:49])=[CH:24][CH:25]=1
Reactant: Cc1cc(C)c2c(C#N)cn(C(c3ccccc3)c3ccc(F)cc3)c2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: Cc1cc(C)c2c(C#N)c(C=O)n(C(c3ccccc3)c3ccc(F)cc3)c2n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (4.46 ml, 34.0 mmol) in tetrahydrofuran (50 ml) was added a 1.6 N solution of butyllithium in hexane (21.3 ml, 34.0 mmol) at −78° C., and the mixture was stirred at −78° C. for 15 minutes. To the resultant solution was added dropwise 1-[(4-fluorophenyl)(phenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (9.35 g, 26.3 mmol) at −78° C., and the mixture was stirred at −78° C. for 30 minutes. Dimethylformamide (5.26 ml, 68.0 mmol) was added thereto, the resulting mixture was stirred at room temperature for 1.5 hours, poured into iced water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the objective product as a solid material.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.C(O)(C)(C)C.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)CCl>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[C:9]([CH:10]=[CH:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2[C@@H](F)C[C@]2(C)C(=O)CC[C@@H]12

Procedure:
2.3 g. of 11β-fluoro-4-androstene-3,17-dione is stirred under reflux in 25 ml. of tert.-butanol and 15 ml. of ethylene chloride with 4 g. of chloranil and 50 mg. of p-toluenesulfonic acid for 6 hours. After the reaction mixture has been worked up as described in Example 16 and chromatographed on silica gel with acetone/hexane, 1.2 g. of 11β-fluoro-4,6-androstadiene-3,17-dione is obtained. UV: ε280 = 25,600.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH3:9][O:10][C:11]([C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N+:20]2[CH3:26])=[CH:15][CH:14]=1)=[O:12].[BH4-].[Na+]>CO>[CH3:26][N:20]1[C:21]2[C:16](=[CH:15][CH:14]=[C:13]([C:11]([O:10][CH3:9])=[O:12])[C:22]=2[N+:23]([O-:25])=[O:24])[CH:17]=[CH:18][CH2:19]1
Reactant: COC(=O)c1ccc2ccc[n+](C)c2c1[N+](=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1[N+](=O)[O-])N(C)CC=C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(methoxycarbonyl)-1-methyl-8-nitroquinolinium trifluoromethanesulfonate (2.10 g, 5.30 mmol) in MeOH (27 mL) at 0° C. was added NaBH4 (200 mg, 5.30 mmol). The mixture was stirred at rt for 1 h. The resulting solution was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated to afford methyl 1-methyl-8-nitro-1,2-dihydroquinoline-7-carboxylate in pure form.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])O.[Na+].[Br:22][C:23]([CH3:28])([CH3:27])[C:24](Br)=[O:25]>C(Cl)(Cl)Cl.O1CCCC1>[Br:22][C:23]([CH3:28])([CH3:27])[C:24]([NH:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]([C:12]([F:13])([F:14])[F:15])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:25]
Reactant: CC(C)(Br)C(=O)Br
Reactant: COC(=O)c1cc(N)c(O)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)C(C)(C)Br)c(O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
Methyl 5-amino-4-hydroxy-2-(trifluoromethyl)benzoate (53.0 g) was dissolved in chloroform (200 ml) and tetrahydrofuran (200 ml), and thereto was added an aqueous sodium hydrogen carbonate solution (27.60 g/240 ml), and the mixture was vigorously stirred. The mixture was cooled in an ice-bath, and thereto was slowly added dropwise 2-bromoisobutyryl bromide (65.5 g), and the mixture was stirred for 30 minutes. The mixture was warmed to room temperature, and further stirred for 2.5 hours. After the reaction was complete, the mixture was extracted twice with chloroform (300 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give methyl 5-[(2-bromo-2-methylpropanoyl)amino]-4-hydroxy-2-(trifluoromethyl)benzoate. This crude product was diluted in N,N-dimethylformamide (500 ml), and thereto was added potassium carbonate (60.53 g), and the mixture was stirred at 50° C. for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, and the obtained solid was removed by filtration. To the filtrate was added ethyl acetate (500 ml), and the mixture was washed with a 1N hydrochloric acid (500 ml) and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was crystallized from ethyl acetate/hexane (5/1, 200 ml) to give the title compound (48.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][CH:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]2=[O:37])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)[CH:9]=1.BrC1C=CN=C(OC2COC3=NC([N+]([O-])=O)=CN3C2)C=1>>[F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]2=[O:37])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][C@@H:15]2[CH2:20][O:19][C:18]3=[N:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][N:17]3[CH2:16]2)[CH:9]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccnc(OC4COc5nc([N+](=O)[O-])cn5C4)c3)c(F)c2)C(=O)O1
Agent: O=[N+]([O-])c1cn2c(n1)OCC(Oc1cc(Br)ccn1)C2
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccnc(O[C@@H]4COc5nc([N+](=O)[O-])cn5C4)c3)c(F)c2)C(=O)O1

Procedure:
N-(3-{3-Fluoro-4-[2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-pyridin-4-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide. The title compound was prepared by following the same procedure as described in the preparation of Example 7, except 6-(4-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine was used in place of 6-(5-bromo-pyridin-2-yloxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine. ESI MS m/z 513.3 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=5.2 Hz, 1H), 7.57 (dd, J=13.2, 2.0 Hz, 1H), 7.46 (d, J=5.2 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.29 (dd, J=9.2, 2.8 Hz, 1H), 7.17 (m, 1H), 6.94 (s, 1H), 6.07 (t, J=5.2 Hz, 1H), 5.78-5.79 (m, 1H), 4.85-4.82 (m, 2H), 4.55 (d, J=12.4 Hz, 1H), 4.40 (d, J=2.4 Hz, 2H), 3.82 (dd, J=8.8, 6.4 Hz, 1H), 3.72-3.63 (m, 2H), 2.03 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[Si:14]([O:31][CH2:32][C@@H:33]([N:36]1[C@H:41]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C@@H:40]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=2)[CH2:39][C@:38]([CH3:58])([CH:56]=O)[C:37]1=[O:59])[CH2:34][CH3:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Si:14]([O:31][CH2:32][C@@H:33]([N:36]1[C@H:41]([C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[C@@H:40]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=2)[CH2:39][C@@:38](/[CH:58]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])([CH3:56])[C:37]1=[O:59])[CH2:34][CH3:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(C=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(/C=C/C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of THF (4 mL) and sodium hydride (16 mg, 0.40 mmol, 60% dispersion in oil) under a nitrogen atmosphere at 0° C. was added trimethyl phosphonoacetate (61 μL, 0.43 mmol) dropwise over 30 seconds. The mixture was allowed to warm to rt for 30 minutes. A solution of (3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carbaldehyde (205 mg, 0.305 mmol; Example 248, Step C) in THF (3 mL) was added. The resulting mixture was stirred at rt for 2 hours. The reaction was partitioned between EtOAc (80 mL) and water (40 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (SiO2, hexanes:EtOAc, 1:0 to 8:2) gave the title compound. Mass Spectrum (ESI) m/z=728.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.CC(C)(C)C(Cl)=O.[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Li]CCCC.[O-][Mn](=O)(=O)=O.[K+]>C1COCC1>[CH2:28]([C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[N:36]1[C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: CC(C)(C)C(=O)Cl
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
In a 1000 mL flask under N2, 2-(3-chlorophenyl)acetic acid (3.50 g, 20.51 mmol) was added to dry THF (300 mL), and the contents were cooled to 0° C. DIEA (3.93 mL, 22.6 mmol) was added to the stirring solution, followed by portionwise addition of trimethylacetyl chloride (2.60 g, 21.5 mmol). In a separate flask, (R)-4-benzyloxazolidin-2-one (3.82 g, 21.5 mmol) was added to dry THF (75 mL) and cooled to −78° C. under N2. n-BuLi (8.21 mL, 20.5 mmol) was added to this cold stirring solution, and the whole contents were stirred for 30 minutes at −78° C. This solution was then slowly added to the mixed anhydride at 0° C. The reaction was stirred for 2 hours and determined complete by TLC (25% ethyl acetate/hexanes, KMnO4 stain). The reaction was quenched with water (250 mL) and diluted with ethyl acetate (250 mL). The layers were separated, and the organics were washed with brine (100 mL), dried (MgSO4) and concentrated to an oil. The oil was purified by flash chromatography (10% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) to give (R)-4-benzyl-3-(2-(3-chlorophenyl)acetyl)oxazolidin-2-one (1.99 g, 6.03 mmol, 29.4% yield). 1H NMR (400 MHz, CDCl3) 7.37-7.20 (m, 7H), 7.14 (d, J=6.64 Hz, 2H), 4.73-4.64 (m, 1H), 4.28 (dd, J1=16.00 Hz, J2=33.97 Hz, 2H), 4.22-4.16 (m, 2H), 3.27 (dd, J1=3.12 Hz, J2=13.27 Hz, 1H), 2.77 (dd, J1=9.37 Hz, J2=13.27 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14]C(=O)C(C)(C)C>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14]
Reactant: CC(C)(C)C(=O)Nc1cnccc1-c1ccccc1Cl
Agent: Cl
Product: Nc1cnccc1-c1ccccc1Cl
Temperature: 92.5 °C
Yield: 94.6 %

Procedure:
A suspension of 22.2 g (77 mmol) N-[4-(2-chloro-phenyl)-pyridin-3-yl]-2,2-dimethyl-propionamide in 730 ml 3 N hydrochloric acid solution was heated to 90-95° C. overnight. The reaction mixture was cooled to room temperature, washed with three 130 ml portions diethyl ether and 500 ml ethyl acetate were added. The aqueous phase was adjusted to pH 7-8 by addition of 28% sodium hydroxide solution under ice cooling. The organic phase was separated and the product was extracted with three 200 ml portions of ethyl acetate. The combined organic layers were dried (magnesium sulfate) and evaporated to give 14.9 g (95%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@@H:20]3[CH2:24][NH:23][CH2:22][C@@H:21]3[C:25]([O:27][CH3:28])=[O:26])=[O:18])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH2:38](Br)[C:39]#[CH:40]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@@H:20]3[CH2:24][N:23]([CH2:40][C:39]#[CH:38])[CH2:22][C@@H:21]3[C:25]([O:27][CH3:28])=[O:26])=[O:18])=[CH:29][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)[C@H]1CNC[C@H]1NC(=O)c1ccc(Cc2cc(C)nc3ccccc23)cc1
Reactant: C#CCBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCN1C[C@H](C(=O)OC)[C@H](NC(=O)c2ccc(Cc3cc(C)nc4ccccc34)cc2)C1
Temperature: 0 °C
Yield: 54.4 %

Procedure:
The TFA salt (403a) (92 mg, 0.15 mmol) was dissolved in 2 mL of chloroform and the solution was cooled to 0° C. Triethylamine (88 mg, 122 μL, 0.87 mmol) and propargyl bromide (65 mg, 50 μL, 0.44 mmol) were added subsequently. The mixture was stirred until disappearance of compound (403a). The solution was diluted with ethyl acetate and washed with H2O and brine, and dried over MgSO4. After filtration and concentration, the residue was purified on silica gel to provide methyl (3S,4S)-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxylate (36 mg, 56%). MS (AP+): 442 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=O)[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1.[NH2:19][CH2:20][C:21]1[N:26]=[CH:25][C:24]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[C:36]([F:39])([F:38])[F:37])=[CH:23][C:22]=1[F:40]>>[NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([NH:10][C@@:11]1([C:16](=[O:18])[NH:19][CH2:20][C:21]2[C:22]([F:40])=[CH:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[C:36]([F:39])([F:38])[F:37])=[CH:25][N:26]=2)[CH2:15][CH2:14][O:13][CH2:12]1)=[O:9]
Reactant: COc1ccc(Nc2cnc(CN)c(F)c2)c(C(F)(F)F)c1
Reactant: Nc1cncc(C(=O)N[C@@]2(C(=O)O)CCOC2)c1
Product: COc1ccc(Nc2cnc(CNC(=O)[C@]3(NC(=O)c4cncc(N)c4)CCOC3)c(F)c2)c(C(F)(F)F)c1
Yield: 34 %

Procedure:
Analogously to Example 1e), (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid (from 2b) was reacted with (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-methoxy-2-trifluoromethyl-phenyl)-amine. The product was obtained in a yield of 34% of theory.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:8]([CH:10]=[CH:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])=[CH:14][CH:13]=1)=[O:9].[H][H]>C(O)(=O)C.[Pd]>[NH:3]1[CH2:4][CH2:5][CH2:6][N:1]=[C:2]1[NH:7][C:8]([CH2:10][CH2:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C(C=Cc1ccc(C(=O)OCc2ccccc2)cc1)Nc1ncccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(CCc1ccc(C(=O)O)cc1)NC1=NCCCN1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
305 g (0.85 mol) of benzyl 4-(2-(pyrimidin-2-ylcarbamoyl)vinyl)benzoate were hydrogenated in a 20 l Būchi autoclave in 8 l of 20% aqueous acetic acid in the presence of 25 g of 10% palladium/charcoal at, 40° C. under a hydrogen pressure of 2 bar. After 6 h and uptake of 65.76 l of hydrogen the reaction was finished. After standing overnight the mixture was warmed to 70° C. and the catalyst filtered off. The autoclave was washed with 3 l of 20% aqueous acetic acid at 70° C. The catalyst was washed with 1.5 l of 20% aqueous acetic acid at 70° C. The filtrate was evaporated under reduced pressure in a rotary evaporator and the residue was dissolved in 1 l of water with heating. Upon cooling to room temperature the product precipitated. The mixture was cooled to 0° C. to 5° C., the product was filtered off, washed with cold water and dried under reduced pressure at 50° C. Yield: 212 g (90.6%).