Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl>[CH:21]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]4[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:28]5[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[O:34])[CH:7]=[CH:6][CH:5]=4)[N:14]=3)[NH:20][N:19]=2)[CH2:23][CH2:22]1
Reactant: Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of N2-(3-aminophenyl)-N4-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine (0.014 g, 0.046 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this 3-(trifluoromethyl)phenyl isocyanate (0.006 mL, 0.046 mmol) diluted in CH2Cl2 (5 mL) was added drop wise. The reaction was allowed to warm to room temperature and left stirring for 12 hours. The reaction proceeded until completion as judged by TLC and LC-MS. The reaction mixture was concentrated in vacuo, resuspended in 50:50 H20-CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to afford AD77. ESI-MS m/z [M+H]+ found 495.4, calculated 495.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1(O)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:28]1([O:18][C:17](=[O:19])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OC1CCCC1
Temperature: 0 °C
Reaction time: 22 h
Yield: 68.4 %

Procedure:
To a solution of (S)-3-(4-Benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid (10 g, 26.9 mmol) in DMF (100 ml) was added cyclopentanol (4.6 g, 53.8 mmol) and DMAP (329 mg, 2.69 mmol). The solution was cooled down to 0° C. and EDC.HCl (5.4 g, 28.2 mmol) was added. The reaction mixture was then stirred at r.t. for 22 hours. Water (100 ml) and EtOAc (100 ml) were added and the phases were separated. The aqueous phase was extracted with EtOAc (2×80 ml). The organics were washed with water (3×50 ml) and brine (50 ml), then dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified on column (Heptane/EtOAc 7:3) to yield the title compound (8.09 g, 68.4%). LCMS purity 96.6%, m/z 462 [M++Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1cccnc1
Agent: N
Product: Clc1cncc(-c2cc(-c3cccnc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 3-ethynylpyridine (Aldrich, 31.0 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.65 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.92 (s, 1H), 8.30 (dt, J=7.7, 2.2, 2.0 Hz, 1H), 8.45 (t, J=2.2 Hz, 1H), 8.75 (dd, J=4.8, 1.6 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H), 9.13 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+, 258 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccc(-c2ncc(Br)cn2)cc1)C(=O)O)OCc1ccccc1
Yield: 99.9 %

Procedure:
Prepared using General Procedure 8: To a stirred solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoate (1.08 g, 2.11 mmol) INT-7 in DCM (10 mL) was added TFA (5 mL). After 16 h the mixture was diluted with toluene (10 mL) and evaporated. Further toluene (2×10 mL) was evaporated from the residue to afford 962 mg (100%) of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propanoic acid as an off-white solid. LCMS-ESI (m/z) calculated for C21H18BrN3O4: 455.1. found 456.0 [M+H]+, tR=5.81 min (Method 10).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24](O)=[O:25])[N:21]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[NH:52][C:53](=[NH:55])[CH3:54]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]3[O:25][N:55]=[C:53]([CH3:54])[N:52]=3)[N:21]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=N)NO
Reactant: O=C(O)CCc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(CCc2csc(Nc3ncc(Br)cc3OCc3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a mixture of 3-(2-(3-(benzyloxy)-5-bromopyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.200 g, 0.461 mmol), N,N-diisopropylethylamine (0.0882 ml, 0.507 mmol) in DMF (5 mL) at ambient temperature was added N-((dimethylamino)fluoromethylene)-N-methylmethanaminium hexafluorophosphate(V) (0.122 g, 0.461 mmol). The mixture was stirred for 30 minutes at ambient temperature, and then N-hydroxyacetamidine (0.0375 g, 0.507 mmol) was added in one portion. The reaction mixture was heated at 110° C. overnight and then cooled to ambient temperature. Ethyl acetate was added and the organic layer was washed with water. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a residue that was purified on a silica gel column, eluting with 40% EtOAc/Hexanes. The isolated material was recrystallized from EtOAc/Hexanes and dried under high vacuum to afford 3-(benzyloxy)-5-bromo-N-(4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)thiazol-2-yl)pyridin-2-amine (0.110 g, 50% yield) as a tan solid. 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 3.05 (t, J=7.6 Hz, 2H), 3.26 (t, J=7.6 Hz, 2H), 5.29 (s, 2H), 6.73 (s, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.42 (t, J=7.2 Hz, 2H), 7.58 (s, 1H), 7.60 (s, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 10.32 (s, 1H); Mass Spectrum (apci) 472 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:34])[CH:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:22]=2)C(O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:54]([CH2:57]C)CC)C.[OH2:59]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:34][C:57](=[O:59])[NH:54][CH:16]2[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:33])([F:32])[CH:29]([F:30])[F:31])[CH:22]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Reactant: O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2ccc(OCc3ccccc3)cc2)O1

Procedure:
To a solution of (2RS,3RS)-3-[4-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoic acid (21.0 g, 43.9 mmol) in tetrahydrofuran (300 ml) were added diphenylphosphoryl azide (10.4 ml, 48.3 mmol) and triethylamine (9.2 ml, 65.9 mmol), ant the mixture was heated under reflux for 2 hrs. The reaction solution was allowed to cool and water (400 ml) was added. The mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (16.4 g, 79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:40])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[N:24](C(OC(C)(C)C)=O)[C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:40])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:24][C:25]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:26][CH:27]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
t-Butyl 2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (7.16 g, 12.2 mmol) synthesized in Example (1h) was dissolved in dichloromethane (15 mL), and cooled to 0° C. Trifluoroacetic acid (30 mL) was added dropwise with stirring under nitrogen atmosphere. Stirring was carried out at room temperature for 30 minutes, followed by further stirring at 40° C. for 30 minutes. The solvent was distilled off under reduced pressure followed by dilution with ethyl acetate (300 mL), a saturated aqueous sodium hydrogencarbonate solution (200 mL) was added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired compound (5.21 g, yield 88%) as a pale yellow solid.
Reaction SMILES: N[C:2](N)=[O:3].[CH3:5][C:6]([SiH2:11]Cl)([CH2:9][CH3:10])[CH2:7][CH3:8]>CO>[CH3:5][C:6]([SiH2:11][O:3][CH3:2])([CH2:9][CH3:10])[CH2:7][CH3:8]
Reactant: NC(N)=O
Reactant: CCC(C)(CC)[SiH2]Cl
Solvent: CO
Product: CCC(C)(CC)[SiH2]OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 300 ml 3-necked flask equipped with a magnetic stirrer, a Dimroth condenser and a 50 ml dropping funnel were charged 50 ml of methanol and 4.5 g of urea. To this was added dropwise 7.3 g of 3-methyl-3-(chlorosilyl)pentane obtained above over 15 minutes. After completion of the addition, the resulting mixture was stirred at room temperature for 1 hour while monitoring the reaction by gas chromatography. After evaporation of methanol, the residue. was extracted with 60 ml of hexane. The extraction was repeated 3 times. Then, hexane was distilled off and the residue was used for the following reaction.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:23])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:7]1.ClCl>ClCCl>[Cl:1][C:15]1[CH:16]=[C:17]([C:20](=[O:22])[CH3:21])[CH:18]=[CH:19][C:14]=1[CH:8]1[CH2:7][C:6]([CH3:23])([CH3:5])[CH2:11][C:10]([CH3:12])([CH3:13])[CH2:9]1
Reactant: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)cc1
Reactant: [Cl-]
Agent: ClCl
Agent: [Al+3]
Solvent: ClCCl
Product: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
40.25 g of aluminium chloride are added at 0° C., under an inert atmosphere, to 350 ml of dichloromethane, followed by addition of 5 g of 1-[4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (compound V.1) dissolved in dichloromethane. After stirring for 2 hours at 0° C., 17.1 ml of chlorine gas (d=1.565, measured in the liquid state at −78° C.) are bubbled into the reaction. After warming to room temperature, a water/ice mixture is added to the reaction mixture. The resulting mixture is extracted with dichloromethane, the phases are separated after settling has taken place, and the organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified on a column of silica gel, eluting with a 7/3 (v/v) cyclohexane/dichloromethane mixutre; yield=74%; m.p.=64° C.
Reaction SMILES: [OH:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.C(Cl)Cl.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>O>[C:33]([O:1][C:2]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:22])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1cc2c(cc1C=O)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@@H]1CC2
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 3-hydroxyestra-1,3,5(10)-trien-17-one-2-carboxaldehyde (60, 1.92 g, 6.43 mmol) of CH2Cl2 (30 mL) was added triethylamine (2.3 mL, 16 mmol) and acetic anhydride (0.94 mL, 9.6 mmol) at room temperature. The reaction mixture was stirred for 16 h, H2O was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (2:1→3:2, v/v) to afford 2.08 g of 61 (95% yield) mp: 179-181° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: Brc1ccccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
2-bromopyridine (14.9 g, 93.1 mmol) in anhydrous THF (700 mL) was cooled to −78° C. under a stream of nitrogen gas, n-BuLi in hexane (54 mL) were added thereto and the mixture was stirred for 30 min. Tributyltin chloride (29 mL, 108 mmol) was added and the mixture was stirred, at −78° C. for 2 hours and afterwards at −20° C. for 3 hours. It was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and the solvent was evaporated. The residue was purified by chromatography (petroleum ether/ethyl acetate=9/1) to give 2-(tributylstannyl)pyridine (12 g, yield 34%) as a yellow liquid, LC-MS (ESI) m/z: 370 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:31]([O:35][C:36](=[O:39])[CH2:37]Cl)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[C:31]([O:35][C:36](=[O:39])[CH2:37][N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])([CH3:34])([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with tert-butylchloroacetate and cesium carbonate in N,N-dimethylacetamide to give [[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetic acid tert-butyl ester as a light yellow oil. MS: 606.6 ([M+NH4]+)
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH2:18][CH2:19][CH2:20][OH:21])[C:8](=[O:17])[C:9]1[C:14]([I:15])=[CH:13][CH:12]=[N:11][C:10]=1Cl.[H-].[Na+].O>O1CCCC1>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]1[CH2:18][CH2:19][CH2:20][O:21][C:10]2[N:11]=[CH:12][CH:13]=[C:14]([I:15])[C:9]=2[C:8]1=[O:17]
Reactant: O=C(c1c(I)ccnc1Cl)N(CCCO)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
N-[3,5-bis(trifluoromethyl)benzyl]-2-chloro-N-(3-hydroxypropyl)-4-iodonicotinamide (6.86 g) was dissolved in tetrahydrofuran (60 mL). While the mixture was chilled on an ice bath, sodium hydride (581 mg, 60% oil suspension) was added and the mixture was stirred for 30 min. Subsequently, the temperature of the mixture was allowed to rise to room temperature and the mixture was stirred for another hour. While the mixture was chilled on an ice bath, water was added and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and was then dried on anhydrous sodium sulfate. The solvent was removed and the resulting residue was purified on a silica gel column chromatography (ethyl acetate:n-hexane=2:1) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (2.69 g, 42%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:41]=2)[CH:36]=[C:35]1[C:48]([O:50][CH2:51][CH3:52])=[O:49].[C:53]([O:57][C:58]([NH:60][CH2:61][C:62]1([CH2:75]O)[CH2:67][CH2:66][N:65]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:64][CH2:63]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C1COCC1>[C:71]([O:70][C:68]([N:65]1[CH2:66][CH2:67][C:62]([CH2:75][N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:41]=3)[CH:36]=[C:35]2[C:48]([O:50][CH2:51][CH3:52])=[O:49])([CH2:61][NH:60][C:58]([O:57][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:59])[CH2:63][CH2:64]1)=[O:69])([CH3:73])([CH3:74])[CH3:72]
Reactant: CC(C)(C)OC(=O)NCC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
A solution of triphenylphosphine (19.4 g, 74.1 mmol) and DIAD (14.05 mL, 74.1 mmol) in THF (700 mL) is cooled to 0° C. and stirred for 10 min. Diethyl 1H-indole-2,6-dicarboxylate (15.47 g, 59.3 mmol) is added and reaction mixture is stirred for another 10 min. tert-Butyl 4-{[(tert-butoxycarbonyl)amino]methyl}-4-(hydroxymethyl)piperidine-1-carboxylate (17 g, 49.4 mmol) is added and the reaction mixture is stirred for 48 h at room temperature. The mixture is partitioned between water and ethyl acetate. and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (2×200 mL). The combined organic layers are dried (Na2SO4), and concentrated. The residue is purified by flash column chromatography using 15% EtOAc in petroleum ether to afford the title compound (17 g, 32%) as a dark brown oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:22][CH2:21][CH2:20][CH:16]1[C:17]([OH:19])=[O:18]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([O:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCN1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
Benzyl bromide (2 eq.) and K2CO3 (2.5 eq) were added to a solution (0.6 M) of DL-proline in DMF. The reaction was stirred at 100° C. overnight. The solution was allowed to cool to RT and then diluted with EtOAc and washed with 1 N HCl, brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 90:10) to afford the product (43%). (ES+) m/z 296 (M+H)+
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](O)=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1>C1(C)C=CC=CC=1>[Cl:8][C:14]1[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]([F:10])=[CH:12][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a stirred solution of N,N-dimethylformamide (2.02, 26.1 mmol) in toluene (20 mL) was added thionyl chloride (2.86 mL, 39.2 mmol) at room temperature. After 10 min, 4-fluoro-2,6-dinitrophenol (5.27 g, 26.1 mmol) was added and the mixture was stirred for 7 h at 80° C. The reaction mixture was concentrated in vacuo, and the resulting solid was washed with ethanol to give the title compound as a pale yellow solid (3.24 g, 14.7 mmol, 56%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]2[NH:12][N:11]=[N:10][N:2]=2)=[CH:4][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2nnn[nH]2)cc1
Temperature: 140 °C
Yield: 78.6 %

Procedure:
A mixture of 4-cyanophenol (4.8 g, 40 mmol), sodium azide (7.8 g, 120 mmol) and triethylamine hydrochloride (8.24 g, 60 mmol) in 1-methyl-2-pyrrolidinone (40 ml) was stirred and heated in an oil bath at 140° C. for five hours. The cooled solution was acidified with 2M hydrochloric acid (200 ml) and extracted with ethyl acetate (3×100 ml). The combined ethyl acetate extracts were washed with water (3×100 ml), dried over anhydrous magnesium sulphate, filtered and evaporated to a fawn solid which was crystallised from 50% v/v ethyl acetate in isohexane to give the title compound (5.1 g.) NMR d (d6-DMSO) 6.95 (2H,d), 7.85 (2H,d), 10.13 (1H,br); MS[MH]+ 163