Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[Cl:24][C:25]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:32]=[C:31]([O:33][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: COc1ccc(-c2nc(COC3CCCCO3)c(CCl)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COC3CCCCO3)c(COc3ccc(C#N)c(Cl)c3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
2.5 g 5-Chloromethyl-2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole and 1.48 g 2-chloro-4-hydroxybenzonitrile were dissolved in 20 ml dimethylformamide. 4.82 g Cesium carbonate were added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with 200 ml ethyl acetate and washed five times with portions of 50 ml water and brine. The organic phase was dried over MgSO4 and the solvent was evaporated in vacuo to obtain 4.0 g crude 2-chloro-4-[2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-5-ylmethoxy]-benzonitrile. This material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]3[C:18]([CH2:19][C:20](=[O:44])[N:21]([CH2:29][C:30]([N:32]([CH:41]([CH3:43])[CH3:42])[C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:31])[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=43)=[N:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH:54]=O)=[CH:46]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]3[C:18]([C:19](=[CH:54][C:47]4[C:48]5[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=5)[NH:45][CH:46]=4)[C:20](=[O:44])[N:21]([CH2:29][C:30]([N:32]([CH:41]([CH3:42])[CH3:43])[C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:31])[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=43)=[N:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4cccc(OCc5ccccc5)c4)n3-c3ccccc32)C(C)C)cn1
Reactant: O=Cc1c[nH]c2ccccc12
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccccc34)c3nnc(-c4cccc(OCc5ccccc5)c4)n3-c3ccccc32)C(C)C)cn1
Yield: 38.3 %

Procedure:
Following the procedure described for Example 1 (A), Step A, 2-[1-(3-benzyloxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 6) (129 mg, 0.219 mmol) was condensed with 1H-indole-3-carbaldehyde (70 mg, 0.48 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (10% EtOAc in hexanes to 100% EtOAc) yielded 60 mg of 2-[1-(3-benzyloxy-phenyl)-4-(1H-indol-3-ylmethylene)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.13 (m, 1H), 7.64 (m, 2H), 7.23-7.48 (m, 13H), 7.13 (m, 3H), 6.93 (m, 2H), 4.94 (m, 2H), 4.85 (m, 1H), 4.63 (m, 1H), 4.20-4.40 (m, 1H), 3.96 (m, 1H), 3.85 (d, 1H), 0.90-1.05 (m, 6H); MS 716.5 (M+1), 714.6 (M−1)
Reaction SMILES: [N:1]1([C:7](=[O:28])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=C[C:36]2[N:41](O)N=[N:39][C:37]=2C=1.Cl.NCC#N.CN1CCOCC1>>[C:37]([CH2:36][NH:41][C:10](=[O:12])[CH:9]([CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:25])[F:26])(=[O:15])=[O:16])[CH2:8][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:28])#[N:39]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1C(F)(F)F
Agent: Cl
Agent: N#CCN
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: N#CCNC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture comprised of 4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzylsulfonylmethyl)-butyric acid (200 mg, 0.47 mmol), prepared as in reference 5, EDC (200 mg, 1.05 mmol), HOBt (200 mg, 1.3 mmol), and aminoacetonitrile hydrochloride (150 mg, 1.6 mmol) was treated with dichloromethyl (4 mL) and 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate and evaporated under vacuum. The product was crystallized from ethyl acetate/hexane to yield N-cyanomethyl-4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzyl-sulfonylmethyl)-butyramide (156 mg) as a yellowish solid; 1H NMR: (DMSO) 8.87 (t, J=5.5 Hz, 1H), 7.81–7.57 (m, 4H), 4.74 (d, J=14.5 Hz, 1H), 4.67 (d, J=14.5 Hz, 1H), 4.13 (d, J=5.5 Hz, 2H), 3.63–3.26 (m, 11H), 2.75 (dd, J=6.4 Hz, J=16.8 Hz, 1H), 2.65 (dd, J=6.2 Hz, J=16.8 Hz, 1H); MS: (M++1) 462;
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:20](O)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[CH:21]12[CH2:20][CH:3]([CH2:4][CH2:5]1)[CH:2]=[C:12]2[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CCO
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: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CC3CCC2C3)C1
Temperature: 95 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (594 mg, 1.81 mmol), bicyclo[2.2.1]-2-hepten-2-ylboronic acid (250 mg, 1.81 mmol), ethanol (2 ml), 2N aqueous sodium carbonate solution (10 ml), and tetrakis(triphenylphosphine)palladium(0) (253 mg, 0.219 mmol) in toluene (20 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (282 mg, 45.6%) as an oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)C1CCOCC1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C3CCOCC3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide.
Reaction SMILES: [O-][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C[Si]([C:21]#[N:22])(C)C.CN(C)C(Cl)=O.C(OCC)(=O)C>[N+](CC)([O-])=O.O>[C:21]([C:7]1[N:2]=[C:3](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC[N+](=O)[O-]
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
tert-Butyl (E)-3-(1-oxido-2-pyridyl)-2-propenoate (2.10 g, 9.5 mmol) was dissolved in nitroethane (10 ml), and trimethylsilyl cyanide (1.88 g, 19.0 mmol) and N,N-dimethylcarbamoyl chloride (2.04 g, 19.0 mmol) were added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (2.18 g, ca. 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:4]([Cl:9])[N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Br)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cc(-c2ccccc2)cc(Cl)n1
Temperature: 80 °C
Yield: 26.8 %

Procedure:
A round-bottomed flask was charged with 4-bromo-2,6-dichloropyridine (Combi-Blocks Inc., 553 mg, 2.437 mmol), phenylboronic acid (446 mg, 3.66 mmol) and trans-dichlorobis(triphenylphosphine)palladium (ii) (27.8 mg, 0.04 mmol). The vial was placed under nitrogen atmosphere using two evacuation/backfill cycles. 1,4-dioxane (12 ml) and sodium carbonate (775 mg, 7.31 mmol) in water (4.1 ml) were added. The reaction mixture was sealed under nitrogen and heated at 80° C. for 1.5 h. The reaction mixture combined with that on pp14 was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined EtOAc layers were dried (Na2SO4) and concentrated. The crude material was dissolved in DCM, and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide 2,6-dichloro-4-phenylpyridine (146 mg, 0.652 mmol, 26.7% yield) as light-yellow oil. MS m/z=224.0 [M]
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:24][Si](C)(C)C)C#N)=[CH:17][CH:16]=1)[CH3:14].[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>COCCOC>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH:29]([OH:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc(C(C#N)O[Si](C)(C)C)cc1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Product: CCc1ccc(C(=O)C(O)c2ccccc2)cc1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
Dissolve 290 ml (2.069 mol) diisopropylamine in 3.6 litres DME and precool to −78° C. Add 820 ml (2.05 mol) n-butyllithium (2.5 M solution in hexane) dropwise in the space of approx. 20 min (temperature<−60° C.). After 15 min at −60° C., add a solution of 435 g (1.864 mol) (4-ethylphenyl)[(trimethylsilyl)oxy]acetonitrile in 1.4 litres DME dropwise (temperature<−60° C.). Stir the mixture for a further 30 min at −60° C., before adding a solution of 189.5 ml (1.864 mol) benzaldehyde in 1.4 litres DME (time approx. 20 min, temperature −60° C.). Heat the mixture over a period of 4 h to RT, before adding 7 litre satd. ammonium chloride solution. Extract the reaction mixture with ethyl acetate. After phase separation, wash the organic phase with satd. ammonium chloride solution, dry, and concentrate by vacuum evaporation. Dissolve the residue in 7 litres dioxan and 5 litres methanol, and add 6 litres 1 N hydrochloric acid. Stir the mixture overnight at RT, then, after adding 11 litres satd. sodium chloride solution, extract with 6.5 litres ethyl acetate. Wash the organic phase with water and with satd. sodium chloride solution, dry, and concentrate by vacuum evaporation. Dissolve the residue in 2 litres diisopropyl ether, add seed crystals and stir for 2 h. The precipitated solid is filtered with suction, washed with 300 ml diisopropyl ether and petroleum ether and dried under vacuum. Concentrate the mother liquor, and after storing for 2 days at 4° C., again filter off the precipitated solid with suction, wash with approx. 100 ml diisopropyl ether and petroleum ether and dry under vacuum. On combining the two solids, 154.9 g (34% of theor.) of the target product is obtained.
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH2:23])[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
2-[2-(4-benzhydryloxy-piperidin-1-yl)-ethyl]-isoindole-1,3-dione (0.548 g, 1.24 mmol) was dissolved in ethanol (2 ml), followed by the addition of hydrazine hydrate (large excess, 2-3 ml). The solution was refluxed for 2 hours. The white solid was precipitated. After cooling to the room temperature, the white solid was filtered off and washed with small amount of ethanol. The filtrates were combined and concentrated. The resulted residue was dissolved in toluene (100 ml). The solution was washed with water (3×20 ml) and dried over anhydrous Na2SO4. After evaporated the solvent, the crude product, 2-(4-benzhydryloxy-piperidin-1-yl)-ethylamine was obtained (0.326 g, 84.4% yield). 1H-NMR (CD3OD, ppm): 7.15-7.40 (m, 10H), 5.58 (s, 1H), 3.46 (m, 1H), 2.77 (m, 2H), 2.72 (t, 2H), 2.40 (t, 2H), 2.18 (m, 2H), 1.89 (m, 2H), 1.70 (m, 2H). ESMS 311.2 (M+1), 333.2 (M+23).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([NH2:16])([C:13]([OH:15])=[O:14])[CH2:8]2.C(N(CC)CC)C.[C:25](=O)([O:41]N1C(=O)CCC1=O)[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2>C(#N)C.O>[C:25]([CH:8]1[C:9]2[C:4](=[C:3]([N:2]([CH3:17])[CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1([NH2:16])[C:13]([OH:15])=[O:14])([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:41]
Reactant: CN(C)c1cccc2c1CCC(N)(C(=O)O)C2
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CN(C)c1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
A mixture of 5-dimethylamino-2-aminotetraline-2-carboxylic acid (1.33 g, 2.15 mmole theoretical), triethylamine (0.40 ml, 2.87 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 0.92 g, 2.73 mmole) in acetonitrile (10 ml) and water (10 ml) was stirred at room temperature for one day. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (400 mg) and triethylamine (0.2 ml) were added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile and the almost neutral mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate. Filtration and concentration gave a crude which was purified by column chromatography (eluted with 2.5→6→10→15→20% methanol/methylene chloride) to give racemic Fmoc-5-dimethylamino-2-aminotetraline-2-carboxylic acid (602 mg, 61% yield over 2 steps) as an off-white solid. HRMS (FAB): C28H28N2O4 (M) calc. 456.2049; observed: 456.2056.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])=[CH:6][C:5]([CH2:32][C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1>>[CH:40]1([CH2:39][O:34][C:33](=[O:35])[CH2:32][C:5]2[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=3[CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:21][C:20]3=[O:31])[C:2]([O:1][CH2:37][CH:38]3[CH2:40][CH2:39]3)=[CH:3][CH:4]=2)[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC2CC2)ccc1OCC1CC1

Procedure:
Prepared according to the procedure described in Example 14, Step 3, using the following starting materials: [6-hydroxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid and (bromomethyl)cyclopropane.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1N2CN3CN(C2)CN1C3.C[CH2:21][O:22]C(C)=O>C(O)(=O)C>[CH:21]([C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:22].[CH:21]([C:9]1[C:2]([OH:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5])=[O:22]
Reactant: N#Cc1ccccc1O
Reactant: CCOC(C)=O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Product: N#Cc1cc(C=O)ccc1O
Product: N#Cc1cccc(C=O)c1O
Temperature: 120 °C
Yield: 9 %
Yield: 19 %

Procedure:
To a solution of 2-hydroxybenzonitrile (4.70 g, 41.6 mmol) in acetic acid (40 mL) was added hexamethylenetetraamine (8.7 g, 62.4 mmol) and the mixture was heated to 120° C. for 2 h. The mixture was cooled to room temperature, followed by a standard aqueous/EtOAc workup and purified by silica gel column chromatography (PE:EA=1:1) to afford 5-formyl-2-hydroxybenzonitrile (Intermediate 47a) as a white powder (540 mg, 9%) and 3-formyl-2-hydroxybenzonitrile (Intermediate 47b) as a white powder (1.17 g, 19%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[C:9]([C:25]2[O:26][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]3)=[CH:28][N:29]=2)[CH:8]=1.CC1(C)C(C)(C)OB([C:48]2[CH:56]=[CH:55][CH:54]=[C:53]3[C:49]=2[CH:50]=[CH:51][NH:52]3)O1>O.C(O)(C)C>[NH:52]1[C:53]2[C:49](=[C:48]([C:7]3[CH:15]=[C:14]4[C:10]([CH:11]=[N:12][N:13]4[S:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)(=[O:17])=[O:18])=[C:9]([C:25]4[O:26][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][N:34]([CH:37]([CH3:38])[CH3:39])[CH2:33][CH2:32]5)=[CH:28][N:29]=4)[CH:8]=3)[CH:56]=[CH:55][CH:54]=2)[CH:50]=[CH:51]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: CC(C)N1CCN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)N1CCN(Cc2cnc(-c3cc(-c4cccc5[nH]ccc45)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of sodium bicarbonate (228.0 g) in water (2.7 L) was added to a suspension of 6-Chloro-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (271.2 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (263.2 g, available from Apollo Scientific Limited) in isopropanol (2.7 L) stirred under nitrogen at ambient temperature. After degassing, via evacuation and flushing with nitrogen, 2′-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex (29.83 g) was added. The mixture was degassed again and was then heated to 90±3° C. and held at this temperature for 2 hours. The mixture was cooled to 20±5° C. over 25 minutes and aged at this temperature overnight. The resultant suspension was filtered, washed with water (1.35 L) and then slurried with toluene (4×1.35 L). The solid was dried under vacuum at 50° C. to give the title compound as grey solid (302.7 g).
Reaction SMILES: ClC([O:4][CH2:5][CH3:6])=O.[CH2:7]([N:14]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/C(O)=O)C=[C:19]([F:21])[CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([N:36](CC)CC)C.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH2:7]([N:14]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[C:17]2[C:6](=[C:19]([F:21])[CH:20]=1)[C:5](=[O:4])[NH:36][CH:23]=[CH:22]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)/C=C/c1cc(F)cc(N(Cc2ccccc2)Cc2ccccc2)c1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1[nH]ccc2cc(N(Cc3ccccc3)Cc3ccccc3)cc(F)c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.7 %

Procedure:
A solution of ethyl chloroformate (0.320 mL, 3.35 mmol) in acetone (5 mL) was added dropwise to a suspension of 19C (1.013 g, 2.80 mmol) in a mixture of acetone (30 mL) and triethylamine (0.90 mL, 6.4 mmol) at 0° C. The reaction mixture was stirred for 45 min and then a solution of sodium azide (0.350 g, 5.4 mmol) in water (8 mL) was added dropwise over 1 h. After an additional 1 h, the reaction was warmed to rt, poured into ice water, and the solid was isolated by filtration and washed with water (Do not allow the solid to dry out). (Caution: this acyl azide intermediate is potentially explosive and should be handled in small quantities behind a safety shield.) The solid was dissolved in DCM, dried (MgSO4), filtered, and the volume reduced to ˜2 mL with a stream of nitrogen. Diphenyl ether (2 mL) was added, and the crude acyl azide solution was used directly. The acyl azide solution was added slowly dropwise via addition funnel to a refluxing mixture of diphenyl ether (8.12 g) and tributylamine (2 mL), internal temperature ˜230° C. A flow of dry nitrogen was maintained through the reaction vessel to a bubbler during the reaction. Reflux was continued for an additional 1 h, after which time the majority of the solvent was removed in vacuo. The residue was cooled to room temperature and hexanes was added. The solid was collected by filtration and washed with hexanes to give 19D (0.830 g, 83%) as an off-white solid. LC-MS m/z: 359.4 (M+H)+.