Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O1CCCC1.O.CO.C(OCC)C>[Si:15]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=C(O)c1ccc(OCCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(C(=O)O)cc1
Reaction time: 8 h
Yield: 88255.9 %

Procedure:
To a solution of 1 (10.0 g, 0.05 mmol) and tert-butyldimethylsilyl chloride (17.50 g, 0.11 mmol 1) in anhydrous N,N-dimethylformamide (45 mL) was quickly added imidazole (14.16 g, 0.21 mmol) under argon. After stirring overnight, the reaction mixture was shaken with diethyl ether (100 mL) and water (300 mL). The ether layer was separated and washed with a saturated NaHCO3 solution (100 mL×2) before drying over anhydrous MgSO4. The solvent was evaporated, and the solid residue was purified by flash column chromatography on silica gel with methylene chloride: hexanes (1:1) as the eluent to afford 2 with silyl-protected hydroxyl and carboxyl groups. This compound was dissolved in tetrahydrofuran: methanol (50 mL: 150 mL) followed by stirring with a solution of K2CO3 (5 g, 36.18 mmol) in water (50 mL) for 1 h. The volume of the solution was reduced by 75% via evaporation under reduced pressure. Brine (150 mL; 120 g NaCl in 500 mL H2O) was added to the resultant slurry, and the pH was adjusted to 5.0 with a 1 M KHSO4 solution. The precipitate was collected by filtration and washed with water before drying under vacuum at 60° C. to yield 2 (13.7 g, 87%). 1H NMR (200 MHz, CDCl3): δ 0.06 (s, 6H, —S1—CH3), δ 0.91 (s, 9H,-SiCCH3)δ 2.01 (quintet, 2H, —CH2—), δ 3.81 (t, 2H, —CH2OAr), δ 4.16 (t, 2 H, HOCH2—), δ 6.96 (d, 2H, aromatic ring), δ 8.06 (d, 2H, aromatic ring).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.[OH-].[NH4+:15]>N.CO>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:2])[NH:15][CH2:11]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: [NH4+]
Agent: N
Agent: [OH-]
Solvent: CO
Product: O=C1NCc2cc(Br)ccc21
Yield: 90 %

Procedure:
4-Bromo-2-bromomethyl-benzoic acid methyl ester (3.70 g) was suspended in 2M NH3 in MeOH (36 mL) and concentrated ammonium hydroxide (12 mL) for eighteen hours. The solid product was filtered to provide the title compound as a colourless solid (2.30 g, 90%). 1H NMR (300M, CDCl3): δ 7.68 (m, 3H), 4.44 (s, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:16][CH:15]([NH:17][C:18]([CH2:20][NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[O:19])[CH2:14]3)[CH2:9][CH2:8]2)[CH:6]=1.[Si:34]([C:38]#[CH:39])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC>CN(C=O)C.[Cu]I>[F:30][C:29]([F:32])([F:31])[C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][CH2:20][C:18](=[O:19])[NH:17][CH:15]1[CH2:16][N:13]([CH:10]2[CH2:11][CH2:12][CH:7]([N:5]3[CH:6]=[C:2]([C:39]#[C:38][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=[N:4]3)[CH2:8][CH2:9]2)[CH2:14]1)=[O:33]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(I)cn3)CC2)C1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
A solution of N-({1-[4-(4-Iodo-pyrazol-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 28, 120 mg, 0.20 mmol), TMS-acetylene (Fluka, 20 mg, 0.40 mmol), Pd(Cl2)dppf (Aldrich, 16 mg, 0.02 mmol), CuI (Aldrich, 3.8 mg, 0.02 mmol) and Et3N (56 uL, 0.40 mmol) in DMF (5 mL) was heated to 80° C. overnight. The reaction was purified column chromatography purification (0-100% ethyl acetate in hexanes with NH3 in MeOH) resulting in the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([B-](F)(F)F)[CH2:12][CH2:13][CH3:14].[K+]>>[CH3:1][C:2]1[CH:9]=[C:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCCC[B-](F)(F)F
Reactant: Cc1cc(Br)ccc1C=O
Agent: [K+]
Product: CCCCc1ccc(C=O)c(C)c1
Yield: 33.8 %

Procedure:
The compound was synthesized as in Example 3.1 using 2-methyl-4-bromobenzaldehyde (113 mg, 0.57 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (113 mg, 0.69 mmol) in place of hexylboronic acid to give 2-methyl-4-butylbenzaldehyde (34 mg, 35%). Used without further characterization.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CCN(C(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>C1COCC1>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(C#N)cc2[N+](=O)[O-])c(OC)c1
Reaction time: 24 h

Procedure:
A solution of 4-fluoro-3-nitrobenzonitrile (5.0 g) in THF (100 mL) was treated with DIEA (6.3 mL) and 2,4-dimethoxybenzylamine (5.0 mL), and then stirred for 24 h. The solvent was evaporated and the crude mixture was dissolved in EtOAc (100 mL). The solution was washed once with 1 M HCl and twice with saturated aqueous NaCl (100 mL each). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (20% EtOAc/DCM) provided 9.25 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:14][C:13](=[O:15])[C@@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[CH2:7][C:6]=2[CH:16]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:22]([O:21][C:17](=[O:20])/[CH:18]=[CH:19]/[C:2]1[CH:3]=[N:4][C:5]2[NH:14][C:13](=[O:15])[C@@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[CH2:7][C:6]=2[CH:16]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1Nc2ncc(Br)cc2CN2CCC[C@H]12
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN1CCC[C@@H]1C(=O)N2
Reaction time: 0.42 h
Yield: 55.7 %

Procedure:
A suspension of (R)-6-bromo-1,2,3,4,9,10a-hexahydro-3a,8,9-triaza-benzo[f]azulen-10-one (3.91 g, 13.8 mmol) in propionitrile (80 mL) and DMF (20 mL) was de-oxygenated with Ar for 25 min. The mixture was treated with tert-butyl acrylate (8.1 mL, 55 mmol) and (i-Pr)2EtN (5.1 mL, 29 mmol) and was de-oxygenated with Ar for 15 min. Pd(OAc)2 (0.31 g, 1.4 mmol) and P(o-tol)3 (0.84 mg, 2.8 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 10 min. The mixture was heated to reflux overnight then allowed to cool. The resulting precipitate was isolated by filtration, dissolved in CH2Cl2, filtered through Celite, and the solvent was removed in vacuo to give the title compound (2.53 g, 56%) as an off-white solid: MS (ESI) m/e 330 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1>[Pd].C(OCC)(=O)C>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: OCCC#Cc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCCCc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
To 4-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-3-yn-1-ol (C61) (0.376 g, 0.967 mmol) in a 100 mL round bottomed flask equipped with a stir bar and septa was added ethyl acetate (9.67 mL) followed by palladium on carbon (0.103 g, 0.0970 mmol). The reaction mixture was evacuated with vacuum and purged with hydrogen (balloon) (2×) and stirred at room temperature overnight. The reaction mixture was filtered through Celite®, washed with ethyl acetate and concentrated to provide the title compound as a white solid (0.363 g, 104%): 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.15-8.08 (m, 2H), 7.94-7.88 (m, 2H), 7.80 (dd, J=8.2, 1.1 Hz, 2H), 7.34-7.28 (m, 2H), 3.74-3.66 (m, 2H), 3.66-3.60 (m, 1H), 2.72 (t, J=7.6 Hz, 2H), 1.81-1.71 (m, 2H), 1.69-1.60 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −62.48; ESIMS m/z 362 ([M+H]+).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]1[CH2:20][CH:21]=[N:22][OH:23]>CN(C=O)C.C(OCC)(=O)C>[O:19]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:9])[N:11]1[CH2:20][C:21]([Cl:1])=[N:22][OH:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2ccccc2C(=O)N1CC=NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CC(Cl)=NO
Temperature: 50 °C
Yield: 98.7 %

Procedure:
N-Chlorosuccinimide (8.50 g, 63.7 mmol) was added to a solution of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanal oxime (13.0 g, 63.7 mmol) in DMF (100 mL), and the solution was heated at 50° C. gently for two hours and allowed to cool to room temperature. The solution was diluted with ethyl acetate and washed three times with water and once with brine, dried over magnesium sulfate, filtered, and concentrated to provide 15.0 g of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxyethanimidoyl chloride as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11](S(C1C=CC=CC=1)(=O)=O)[C:10]1[CH:9]([OH:24])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].C(OCC1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+]>CN(C)C=O.CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: BrCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1c2c(c3cc(Br)ccc31)CCCC2O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3OCc1ccccc1
Reaction time: 0.02 h
Yield: 71 %

Procedure:
To a solution of 6-bromo-9-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-ol (25 mg, 0.06 mmol) in N,N-dimethylformamide (2 mL) was added benzyl bromide (0.5 mL) and sodium hydride (60% in oil, 50 mg, 1.2 mmol). The reaction was stirred 1.0 min and quenched with water (1 mL). The reaction was diluted with ethyl acetate, washed with water, and concentrated to provide 6-bromo-1-[(phenylmethyl)oxy]-9-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbolzole: MS m/z (m−1) 494, 496. The crude benzyl ether was dissolved in methanol (5 mL) and tetrahydrofuran (3 mL) and aqueous sodium hydroxide (5N, 2 mL) and sodium hydroxide pellets (300 mg, 1.1 mmol) were added. The reaction was stirred at 70° C. for 16 h. The reaction was concentrated, diluted with ethyl acetate, washed with water and concentrated. The crude ether was purified by flash chromatography on silica (5% to 10% ethyl acetate/hexanes) to provide 6-bromo-1-[(phenylmethyl)oxy]-2,3,4,9-tetrahydro-1H-carbazole (15 mg, 71%). as an oily white solid: 1H-NMR (DMSO-d6): δ 11.10 (s, 1H), 7.57 (s, 1H), 7.39 (d, 2H), 7.33 (t, 2H), 7.29-7.24 (d, 2H), 7.13 (d, 1H), 4.72-4.61 (m, 3H), 2.69-2.63 (m, 1H), 2.55-2.50 (m, 1H), 1.99-1.91 (m, 3H), 1.78-1.71 (m, 1H); MS m/z (M−1) 354, 356.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(Cc2ccccc2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a suspension of methyl 4-(2-hydroxybenzyl)benzoate (1.5 g) and potassium carbonate (0.94 g) in N,N-dimethylformamide (200 mL) was added benzylbromide (0.81 mL), and the mixture was stirred at 50° C. for 5 hours. An insoluble material was removed by filtration, water and dilute hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give methyl 4-(2-benzyloxybenzyl)benzoate (2.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27]([Cu])#[N:28]>CN(C=O)C.[Cl-].[NH4+]>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:27]#[N:28])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: N#C[Cu]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(C#N)cc1OCC2)c1ccccc1Cl
Temperature: 250 °C

Procedure:
To a solution of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (50 mg, 0.11 mmol) in 1 mL of DMF in a 10 mL microwave vial was added CuCN (30 mg). The reaction vessel was sealed and heated to 250° C. in a microwave for 20 min. The whole was cooled to room temperature, diluted with saturated aqueous ammonium chloride and extracted with ethylacetate. The combined organic extracts were concentrated and the crude residue purified by reverse phase HPLC to give 143. 1H NMR (500 MHz, DMSO-d6) δ 7.65 (m, 2H), 7.58-7.46 (m, 5H), 6.64 (s, 1H), 4.22 (m, 2H), 3.28 (s, 3H), 3.00 (m, 2H). MS: (ESI+) 395.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH2:12][N:13]1[CH2:18][CH2:17][N:16](C(OCC2C=CC=CC=2)=O)[CH2:15][C:14]1=[O:29])=[O:11].[H][H]>CO>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:11])[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]1=[O:29]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: [H][H]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1=O
Reaction time: 4 h

Procedure:
To a solution of compound 31 in methanol (10 mL) 10% palladium on carbon was added. The reaction vessel was charged with hydrogen (40 p.s.i) and agitated for 4 h. The catalyst was removed by filtration and the filtrate was concentrated and purified using column chromatography (1:15 MeOH:DCM) to yield compound 32 as a semi solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH2:13]Br)=[C:11]([O:15][CH2:16][CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:18][CH2:19][CH3:20].[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:22]>CN(C)C=O>[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:13][C:12]3[C:11]([O:15][CH2:16][CH3:17])=[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[C:4]([O:18][CH2:19][CH3:20])[C:3]=3[CH2:2]2)=[CH:30][CH:31]=1)[CH3:22]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOc1c(CBr)c(CBr)c(OCC)c2ccccc12
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2)cc1
Yield: 35.8 %

Procedure:
A solution of 2,3-bis(bromomethyl)-1,4-diethoxy-naphthalene (41 mg, 0.1 mmol) and 4-aminophenylacetic acid ethyl ester (20 mg, 0.11 mmol) in N,N-dimethylformamide (1 ml) was heated at 60° C. under nitrogen for 14 h. The solvent was removed in vacuo and the residue taken up in ethyl acetate (10 ml) and washed with 8% aqueous sodium bicarbonate solution (5 ml). The organic layer was dried over magnesium sulphate and the solvent removed in vacuo. Purification by flash column chromatography on silica gel eluting with 90% cyclohexane/ethyl acetate gave the product as a white solid (15 mg, 36%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([NH:16][C@@H:17]([C:23]([O:25][CH3:26])=[O:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].[C:27](C1NC=CN=1)(=[O:29])[CH3:28].[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[C:9]([O:13][C:14]([NH:16][C@@H:17]([C:23]([O:25][CH3:26])=[O:24])[CH:18]([C:27](=[O:29])[CH3:28])[C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:11])([CH3:12])[CH3:10]
Reactant: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(=O)c1ncc[nH]1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(C(C)=O)[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 38.3 %

Procedure:
A solution of lithium diisopropylamide (30.8%, 10.5 ml, 22 m mol) in hexane was added to a solution of dimethyl (R)-N-tert-butoxycarbonylaspartate (2.61 g, 10 m mol) in tetrahydrofuran (50 ml) at -78° C. in a stream of nitrogen and the mixture was stirred for 10 minutes at -78° C. After stirring for 20 minutes at -40° C., the reaction mixture was again cooled to -78° C., to which a solution of acetylimidazole (1.32 g, 12 m mol) in tetrahydrofuran (15 ml) was added dropwise. After stirring the reaction mixture for 10 minutes, a saturated ammonium chloride solution was added and the resulting mixture was stirred at room temperature. The resultant was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated NaCl solution, dried over sodium sulfate and distilled off under reduced pressure to remove the solvent. The residue was subjected to a silica gel column chromatography (2.5×40 cm; ethyl acetate: hexane=1:3) to obtain dimethyl (R)-N-tert-butoxycarbonyl-3-acetylaspartate (1.16 g, 38%) as colorless oil.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:27]([C@H:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:28]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[C@H:15]([CH3:16])[C@H:27]([C@H:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[OH:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a solution of (R)-4-benzyl-3-propionyloxazolidin-2-one (1.0 equiv.) in DCM (0.13 M) was added TiCl4 (1.0 equiv.) at −40° C. The mixture was stirred at −40° C. for 10 min (yellow suspension), then DIPEA (2.5 equiv.) was added (dark red solution) and stirred at 0° C. for 20 min. (R)-tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (1.0 equiv.) in DCM (0.5 M) was then added dropwise and the resulting mixture was stirred for 1.5 hours. The reaction was quenched by the addition of aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic phase was separated, washed with brine, dried with magnesium sulfate, filtered, and concentrated. The residue was purified via column chromatography eluting with ethyl acetate and hexanes (1:4) to give (R)-tert-butyl 4-((1R,2R)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-2-methyl-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate as the major product (5:2) in 58% yield. LC/MS=363.3 (M+H-Boc), Rt=1.09 min.
Reaction SMILES: [N:1]1([C:5]2[C:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[N:1]1([C:5]2[C:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of methyl 3-(azetidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (60 mg, 0.18 mmol) in methanol (20 mL) was added sodium hydroxide (50 mg, 1.25 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (3N), and the product was precipitated and filtered to give 3-(azetidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (35.3 mg, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:19][CH:20]2[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)[CH:13]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:25]2[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:21][CH:20]2[CH2:19][NH:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNC(CNc2cccnc2)C1
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2CNc2cccnc2)cc1
Reaction time: 1 h

Procedure:
4-Methoxyphenyl isocyanate (85 mg, 0.567 mmol) was added to a solution of tert-butyl 3-((pyridin-3-ylamino)methyl)piperazine-1-carboxylate (166 mg, 0.567 mmol) in CH2Cl2 (4 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, and the material was purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 81.7 mg (26%) of the TFA salt of the title compound as a white solid. LC-MS: RT=5.29 min, [M+H]+=442.2.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:38][CH2:39][C:40]([C:43](OC)=[O:44])([CH3:42])[CH3:41])=[C:12]([CH:14]2[C:19]3([C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH:18]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[CH2:17][C:16](=[O:37])[NH:15]2)[CH:13]=1>C(OCC)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:38][CH2:39][C:40]([CH3:42])([CH3:41])[CH2:43][OH:44])=[C:12]([CH:14]2[C:19]3([C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH:18]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[CH2:17][C:16](=[O:37])[NH:15]2)[CH:13]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(CO)COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.7 %

Procedure:
To a mixture of LiAlH4 (10 mg, 0.26 mmol) in diethyl ether (2 mL) was added racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 276b (40 mg, 0.062 mmol). The mixture was stirred at room temperature for 10 min, quenched with methanol, purified by Prep-HPLC to give title compound (16 mg, 42%). m/z (M+H)+: 617