Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:12][CH:13]3[N:18]([CH3:19])[CH:17]([C:6]2=1)[CH2:16][CH2:15][CH2:14]3.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.C1(C=CC(O)=CC=1)O>CS(C)=O.O>[CH3:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:28][CH2:27][C:24]1[CH:23]=[N:22][C:21]([CH3:20])=[CH:26][CH:25]=1)[C:7]1[CH2:12][CH:13]3[N:18]([CH3:19])[CH:17]([C:6]2=1)[CH2:16][CH2:15][CH2:14]3
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC2CCCC1N2C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A reaction flask with a septum cap was charged with 30% sodium metal dispersion in paraffin wax (0.30 g, 4.0 mmol; Aldrich) and a solution of 2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (0.48 g, 2.0 mmol; Example 114A) in dimethyl sulfoxide (4 mL). The vessel was sealed, flushed with nitrogen, and stirred for 10 minutes. A solution of 2-methyl-5-vinylpyridine (0.238 g, 2.0 mmol; prepared as described in International Publication No. WO 2001017968) and hydroquinone (0.072 g, 0.66 mmol; Aldrich) in anhydrous dimethyl sulfoxide (1.5 mL) was added and the reaction was heated at 100° C. for 72 hours. After cooling the mixture to room temperature, it was poured into water and extracted with ethyl acetate (4×25 mL). The combined organic extracts were washed with brine, concentrated, and purified by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 15 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 0.82-1.00 (m, 1H), 1.17-1.30 (m, 1H), 1.32-1.42 (m, 1H), 1.55-1.64 (m, 1H), 1.78-1.99 (m, 3H), 2.15 (s, 3H), 2.40 (s, 6H), 2.66 (dd, J=17, 7 Hz, 1H), 3.06-3.15 (m, 3H), 4.03 (t, J=3 Hz, 1H), 4.30-4.37 (m, 2H), 6.95 (dd, J=8, 1 Hz, 1H), 7.08-7.14 (m, 2H), 7.26 (d, J=8 Hz, 1H), 7.32 (dd, J=8, 2 Hz, 1H), 7.82 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 360 (M+H)+.
Reaction SMILES: C(OC([N:6]1[CH:10]=[C:9]([C:11]2[CH:34]=[CH:33][C:14]3[N:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])[CH:21]=[CH:22][CH:23]=4)[CH:16]=[N:17][C:13]=3[CH:12]=2)[CH:8]=[N:7]1)C)C.[ClH:35].O>O1CCCC1>[NH:6]1[CH:10]=[C:9]([C:11]2[CH:34]=[CH:33][C:14]3[N:15]([C:18]4[CH:19]=[C:20]([NH:24][C:25]([NH:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26])[CH:21]=[CH:22][CH:23]=4)[CH:16]=[N:17][C:13]=3[CH:12]=2)[CH:8]=[N:7]1.[ClH:35]
Reactant: CCOC(C)n1cc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1
Temperature: 25 °C

Procedure:
The mixture of N-(3-{5-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-1H-benzimidazol-1-yl}phenyl)-N′-(2,2,2-trifluoroethyl)urea (190 mg, 0.40 mmol) and 1.0 M hydrogen chloride in water (3 mL, 3 mmol) in tetrahydrofuran (5 mL) was stirred at r.t. 2 hours. The reaction mixture was concentrated under reduced pressure to dryness to afford the desired compound as HCl salt which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=401.2.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:18]([Sn:22]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])Cl)[CH2:19][CH2:20][CH3:21]>C1COCC1>[C:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Sn:22]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=2)[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: Ic1cc(C2=CCCC2)ccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C2=CCCC2)ccn1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-iodo-4-cyclopent-1-enyl-pyridine (150 mg, 0.55 mmol) in THF (3 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 0.38 mL, 0.61 mmol). The resulting deep orange-brown solution was stirred at −78° C. for 15 min then tributylchlorostannane (0.17 mL, 61 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 min then warmed to room temperature over 30 min, quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to provide 4-cyclopent-1-enyl-2-tributylstannanyl-pyridine as an orange oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]O.S(Cl)([Cl:13])=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(F)c(Br)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CCl)cc1Br
Yield: 64.9 %

Procedure:
41 g (0.2 mol) of 3-bromo-4-fluoro-benzyl alcohol were dissolved in 250 ml of carbon tetrachloride, and 26 g of thionyl chloride were added dropwise at 20° C., while stirring. The mixture was then stirred at 25°-30° C. for 4 hours and the solvent and excess thionyl chloride were subsequently stripped off at 20° C. under a waterpump vacuum. The residue was distilled in vacuo. 29 g (64.9% of theory) of 3-bromo-4-fluoro-benzyl chloride with a boiling point of 85°-87° C./3 mbars were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30](O)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([C:30]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:10][CH2:11][CH2:12][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)[CH:5]=3)=[O:31])[NH:28][CH:29]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: COc1ccc(N)cc1OCCN1CCCC1
Product: COc1ccc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)cc1OCCN1CCCC1
Yield: 74 %

Procedure:
Acylation of 4-methoxy-3-(2-(pyrrolidin-1-yl)ethoxy)benzenamine from step A with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid to generate the title compound in 74% yield was achieved via the procedure described in step C of Example 1. MS (ESI) 440 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:24]#[C:25][CH2:26][O:27][CH3:28])=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:4][CH:3]=1>[Pd].C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:6][CH:7]=1
Reactant: COCC#Cc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Palladium on charcoal (18 mg, 10%) was added to a solution of 5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(3-methoxy-prop-1-ynyl)-nicotinamide (100 mg, 0.25 mmol) in ethylacetate (12 mL). The mixture was hydrogenated for 2 h at room temperature and 0.4 bar positive hydrogen pressure after which the theoretical amount of hydrogen had been consumed. The catalyst was then filtered off and the solvent was evaporated to afford 5-(4-Chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(3-methoxy-propyl)-nicotinamide without further purification as a orange solid 93 mg (92% yield). m/z (ISP+): 403.2, 405.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CN(c1ccc(C(=O)O)c(Cl)c1)S(C)(=O)=O
Product: CN(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)S(C)(=O)=O

Procedure:
100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-methylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide. MS (Q1) 450 (M)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:14][CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CCCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:14][CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2[C@H](c3ccc([N+](=O)[O-])cc3)CC[C@H]2c2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCCCCCC
Product: CC(C)(C)c1ccc(N2[C@H](c3ccc(N)cc3)CC[C@H]2c2ccc(N)cc2)cc1

Procedure:
To a 160 ml Parr stirrer hydrogenation vessel was added (2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine (2 g, 4.49 mmol), followed by 60 ml of THF, and Raney Nickel Grace 2800 (1 g, 50 wt % (dry basis)) under a stream of nitrogen. The reactor was assembled and purged with nitrogen (8×20 psig) followed by purging with hydrogen (8×30 psig). The reactor was then pressurized to 30 psig with hydrogen and agitation (700 rpm) began and continued for a total of 16 h at room temperature. The slurry was filtered by vacuum filtration using a GF/F Whatman glass fiber filter. Evaporation of the filtrate to afford a slurry followed by the addition heptane and filtration gave the crude 4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline, which was dried and used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[CH2:22]([N:24]([CH2:39][CH3:40])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:23]>C(O)C.N1CCCCC1>[CH2:39]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:40]
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (75.6 mg, 56%).
Reaction SMILES: OC1C=C([C@H:16]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[O:17]2)C=C(S(C)(=O)=O)C=1OCCC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:32][O:31][C:23]1[CH:22]=[C:21]([CH:18]2[O:17][CH2:16][CH2:20][CH2:19]2)[CH:26]=[C:25]([O:27][CH3:28])[C:24]=1[O:29][CH3:30]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C2CCCO2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trans-2-(3-hydroxy-5-methylsulfonyl-4-propyloxyphenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (242), 130 mg, 0.28 mmol) was dissolved in dry DMF (1.5 mL) and K2CO3 (58 Mg, 0.42 mmol) was added to it. Stirred, at room temperature under argon, for 30 min and a solution of 241, made above, in 1.0 mL of dry DMF was added. The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with methylene chloride (25 mL) and washed with water (25 mL). The water layer was extracted once with 25 mL of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and concentrated in vacuo to obtain trans-2-13-methylsulfonyl-5-(4-phthalimido-but-2-ynyloxy)-4-propyloxyphenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran, 244, which was used without further purification. 1H-NMR (CDCl3) (5 7.85 (2H, dd, J=5.3, 3.2 Hz), 7.73 (2H, dd, J=5.3, 3.2 Hz), 7.55 (1 H, d, J=2.0 Hz), 7.32 (1 H, d, J=2.0 Hz), 6.62 (2H, s), 5.16-5.21 (2H, m), 4.77 (2H, s), 4.49 (2H, s), 4.11 (2H, t, J=6.8 Hz), 3.89 (6H, s), 3.84 (3H, s), 3.24 (3H, s), 2.41-2.46 (2H, m), 1.80-2.01 4H, m), 1.04 (3H, t, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]CC)=[CH2:9])[C:5]([F:13])=[CH:4][N:3]=1.[OH-].[K+]>Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]([F:13])=[CH:4][N:3]=1
Reactant: C=C(OCC)c1nc(Cl)ncc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(=O)c1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-chloro-4-(1-ethoxyvinyl)-5-fluoropyrimidine (5.23 g, 25.81 mmol) in 3N HCl (100 mL) was stirred at rt for 6 h. Potassium hydroxide (50%) was added to give a cloudy mixture (pH was still less than 1) and extracted cloudy mixture with EtOAc. More potassium hydroxide (50%) was added and extracted with EtOAc. Again, more potassium hydroxide (50%) was added until pH=7 and extracted with EtOAc. The combined organic layer dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 25% EtOAc/Hex) to give the desired product. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=2 Hz, 1H), 2.71 (2, 3H); 19F (376 MHz, CDCl3) δ −138.26.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.CCO.C([O-])([O-])=O.[Na+].[Na+].[N+:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>COCCOC.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.O>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:27]([O-:29])=[O:28])[CH:35]=2)=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 150 °C
Yield: 66.8 %

Procedure:
2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) (100 mg, 0.33 mmol) was weigh out in a microwave vial and dissolved in 3 ml of DME, 2 ml of EtOH and 1.5 ml of water followed by addition of Na2CO3 (70 mg, 0.66 mmol) and 3-nitrophenylboronic acid (67 mg, 0.4 mmol). Pd(PPh3)4 (8 mg, 6.6 μmol) was then added and the tube was immediately sealed. The reaction mixture was heated in a Smith Synthesizer at 150° C. for 5 min. The solution was filtered and the compound purified by preparative HPLC to yield 75 mg (67%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (dd, 2H), 5.2 (broad, 1H), 7.5(d, 2H), 7.6 (d, 3H), 7.9 (d, 1H), 8.2 (dd, 1H), 8.4 (d, 1H). MS (M+H, 341).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH3:28])([CH3:27])[C:19]1=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][CH:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH3:27])([CH3:28])[C:19]1=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)C(=O)N(C(CCO[Si](C)(C)C(C)(C)C)c2ccccc2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C(CCO)c2ccccc2)c2ccccc21
Reaction time: 1 h
Yield: 89.8 %

Procedure:
1-(3-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylpropyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (4.0 g, 9.8 mmol) was dissolved in tetrahydrofuran (50 mL) and tetrabutyl ammonium fluoride (1.0 M in THF, 14.7 mL, 14.7 mmol) was added and the mixture was stirred for 1 hour. Reaction was quenched with saturated aqueous ammonium chloride then saturated sodium bicarbonate was added, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 10-60% ethyl acetate in hexane) to afford 2.6 g (90%) racemic 1-[3-hydroxy-1-phenylpropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one that was resolved by chiral HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([C:18]2[N:23]=[C:22]([N:24]3[C@@H:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][O:26][C:25]3=[O:32])[CH:21]=[CH:20][N:19]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH:33]1([C:39]([NH2:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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]>[CH:33]1([C:39]([NH:41][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([C:18]3[N:23]=[C:22]([N:24]4[C@@H:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][O:26][C:25]4=[O:32])[CH:21]=[CH:20][N:19]=3)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=2)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(Br)cc2)n1
Reactant: NC(=O)C1CCCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(NC(=O)C3CCCCC3)cc2)n1
Temperature: 100 °C
Yield: 58.9 %

Procedure:
In a 5 ml microwave reaction vial was added tert-butyl (S)-1-(4-bromophenyl)ethyl(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)carbamate (101 mg, 0.2 mmol), cyclohexanecarboxamide (30 mg, 0.24 mol), cesium carbonate (91 mg, 0.28 mmol), XANTPHOS (7 mg, 0.012 mmol, strem chemicals), and Pd2(dba)3 (4 mg, 0.02 mmol). The vial was sealed, evacuated and purged with dry nitrogen three times before adding dioxane (1.6 mL). The reaction mixture was heated to 100° C. for 16 hours in an oil bath. After cooling the reaction was diluted with EtOAc (10 mL) and washed with water (10 mL). After separation, the aqueous phase was extracted with EtOAc (3×10 mL). Combined organics were dried over Na2SO4, filtered and concentrated. The crude material was purified through silica gel column chromatography (EtOAc in Heptane 12 to 100%) to give a white solid (65 mg, 58.9% yield).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:11]([OH:23])[C:12](=[O:22])[NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]>O1CCCC1>[OH:23][CH:11]([C@@H:10]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([NH:2][CH3:1])=[O:4])[C:12](=[O:22])[NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]
Reactant: CN=C=O
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCN)NC(=O)OC(C)(C)C)c1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methylisocyanate (0.472 mL, 8.00 mmol) was added to a slurry of tert-butyl (1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate (3.03 g, 8.00 mmol) at 0° C. in anhydrous tetrahydrofuran (60 mL) under nitrogen. The mixture was stirred at 0° C. for 1 h, during which time all solids dissolved. The cold bath was then removed, and the solution was stirred overnight. Volatiles were removed under vacuum, and the resulting foam was further purified by column chromatography on silica gel. Elution with a gradient from 50% to 75% acetone in hexane afforded tert-butyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-{[(methylamino)carbonyl]amino}pentylcarbamate as a white solid after drying under vacuum (3.00 g, 86%). 1H NMR (300 MHz, DMSO-d6) δ 8.06-8.01 (m, 1H); 7.38-7.18 (m, 5H); 6.40 (d, J=10 Hz) and 6.08 (d, J=9 Hz) total 1H, 5.86-5.75 (m, 1H); 5.71-5.51 (m, 2H); 5.01-4.91 (m, 1H); 3.94 (br s) and 3.87 (br s) total 1H, 3.79-3.64 (m, 1H); 3.01-2.81 (m, 2H); 2.54 (d, J=5 Hz, 3H); 1.52-1.16 (m, 18H). ES-LCMS m/z 437 (M+H).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[S:37](Cl)(=[O:39])=[O:38]>N.CO>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[S:37]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1Cl)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9.6 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.05 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2,4-Dichlorobenzenesulfonyl chloride (25 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (1.9 mg). MS m/z 398 [M+H]+.
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:12]([C:15]1[N:19]([CH2:20][C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=2[N:16]=1)([CH3:14])[CH3:13]>CS(C)=O>[O:3]=[C:2]1[NH:1][CH:7]([CH2:8][C:9]([NH:25][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][N:19]3[C:18]4[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=4[N:16]=[C:15]3[CH:12]([CH3:14])[CH3:13])=[CH:27][CH:26]=2)=[O:11])[C:5](=[O:6])[NH:4]1
Reactant: CC(C)c1nc2ccccc2n1Cc1ccc(N)cc1
Reactant: O=C(O)CC1NC(=O)NC1=O
Solvent: CS(C)=O
Product: CC(C)c1nc2ccccc2n1Cc1ccc(NC(=O)CC2NC(=O)NC2=O)cc1
Yield: 90.4 %

Procedure:
Commercially available (+/−)hydantoin-5-acetic acid (11 mg, 0.07 mmol) and 4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]aniline (30 mg, 0.06 mmol) were warmed in 1 mL dry DMSO until dissolved and coupled using GENERAL COUPLING METHOD A. Purified on silica gel using 5% MeOH in EtOAc to give 22 mg (89%) of a white solid. MS found:(M+H)+=406.