Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C.[C:23]([O:31][C@@H:32]1[C@@H:49]([O:50][Si](C(C)(C)C)(C)C)[C@H:48]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C@H:33]1[S:34][C:35]1[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[CH3:45])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:23]([O:31][C@@H:32]1[C@@H:49]([OH:50])[C@H:48]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C@H:33]1[S:34][C:35]1[CH:40]=[C:39]([C:41]([CH3:43])([CH3:44])[CH3:42])[CH:38]=[CH:37][C:36]=1[CH3:45])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(C(C)(C)C)cc1S[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1OC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(C)C)cc1S[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](O)[C@H]1OC(=O)c1ccccc1
Temperature: 35 °C
Reaction time: 72 h

Procedure:
A solution of TBAF.3H2O (1.10 g, 3.48 mmol) and acetic acid (266 μl, 4.64 mmol) in DMF (4 ml) was added to a solution of 29 (430 mg, 0.58 mmol) in DMF (4 ml). The mixture was stirred for 3 days at 35° C. After dilution with Et2O the phases were separated and the organic phase washed with a 0.1 M HCl solution, saturated aqueous NaHCO3 solution and brine. The organic phase was then dried over MgSO4, filtered and concentrated. The product 40 was taken directly to the next step.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:29])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37]C(NC1C(=O)N2[C@H](C(OC(C)(C)C)=O)CCC2=NC=1)=O)C1C=CC=CC=1.COCCl>>[C:1]([O:5][C:6]([C:8]1([CH2:29][O:37][CH3:30])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Agent: COCCl
Product: COCC1(C(=O)OC(C)(C)C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 36 %

Procedure:
According to the procedure for the preparation of intermediate 19a, alkylation of intermediate 1g (250 mg, 0.649 mmol) with methoxymethylchloride afforded 101 mg (36%) of intermediate 23a. MS (ESI) 430.4 (M+H+), 452.4 (M+Na+).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccccc1Oc1ccccc1
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
2-Phenoxybenzoic acid (2.5 g, 11.7 mmol) was dissolved in THF and added dropwise over 15 min to a solution of lithium aluminum hydride (443 mg, 11.7 mmol) in THF. After 5 min, water (0.44 mL) was added slowly, followed by 15% aqueous NaOH (0.44 mL) and water (1.33 mL). The solid was removed by vacuum filtration and the filtrate was concentrated to give the title compound (2.1 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:20][C:21](O)=[O:22])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:21](=[O:22])[CH2:20][C:14]1[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([F:11])[CH:13]=1
Reactant: COc1cc(F)cc(CC(=O)O)c1
Reactant: COc1ccc(OC)cc1
Solvent: O
Product: COc1cc(F)cc(CC(=O)c2cc(OC)ccc2OC)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a solution of 1,4-dimethoxybenzene (2.62 g, 19 mmol) in PPA (10 mL) at room temperature, 2-(3-fluoro-5-methoxyphenyl)acetic acid (2.33 g, 12.6 mmol) was added. The mixture was stirred at 80° C. for 3 h, cooled to room temperature, and then H2O (100 mL) was added. After extraction with ethyl acetate (3×50 mL), the organic phase was dried over Na2SO4, concentrated, and the crude was purified by silica-gel column chromatography (ethyl acetate/petroleum ether=1/4) to give 1.0 g of 1-(2,5-dimethoxyphenyl)-2-(3-fluoro-5-methoxyphenyl)ethanone. LCMS: 305.1 [M+H]+.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1.[CH2:17](I)[CH2:18][CH3:19]>CS(C)=O>[CH2:17]([N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1)[C:11](=[O:16])[CH:12]=[C:13]([CH3:14])[CH3:15])[CH2:18][CH3:19]
Reactant: CCCI
Reactant: CC(C)=CC(=O)Nc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCN(C(=O)C=C(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
44.3 g of powdered potassium hydroxide were suspended in 200 ml of dimethyl sulphoxide and a solution of 50 g of N-(3-bromophenyl)-3,3-dimethyl-acrylamide in 300 ml of DMSO was added dropwise thereto. The mixture was stirred at room temperature for 1 hour and subsequently a solution of 50.3 g of propyl iodide in 200 ml of DMSO was added dropwise thereto. After 2 hours the reaction mixture was poured on to ice-water, extracted three times with ethyl acetate, the organic phase was washed several times with water, dried and evaporated. After filtration of the crude product over a silica gel column (eluent hexane/ethyl acetate 9:1), 58 g of N-propyl-N-(3-bromophenyl)-3,3-dimethyl-acrylamide were obtained as a yellow oil. This product was dissolved in 1.5 l of petroleum ether (high boiling). 52.3 g of aluminium chloride were added portionwise thereto while stirring and the mixture was subsequently heated at reflux for 2.5 hours. After cooling to 0°-5° C. 500 ml of ice-cold 1N hydrochloric acid were added dropwise thereto, the mixture was diluted with water and extracted several times with ether. The yellow oil obtained after drying and evaporation of the solvent was a 6:4 mixture of 5-bromo-3,4-dihydro-4,4-dimethyl-1-propyl-2(1H)-quinolinone. It was filtered over a silica gel column (eluent hexane/5% ethyl acetate) and taken up in a small amount of hexane. After seeding with the 7-bromo compound above, 12.2 g of pure 7-bromo-3,4-dihydro-4,4-dimethyl-1-propyl-2(1H)-quinolinone crystallized in the cold in colourless crystals, m.p. 50°-51° C.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:29]3[CH2:30][CH2:31][CH:26]([NH:25][CH:24]([C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=4)[C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[CH2:27][CH2:28]3)([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: Fc1ccc(C(NC2CCNCC2)c2ccc(F)cc2)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(NC(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Temperature: 172 °C
Reaction time: 4.5 h
Yield: 38.9 %

Procedure:
Under argon gas, a suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g), N-[bis(4-fluorophenyl)methyl]-4-piperidinamine (4.5 g), and potassium carbonate (1.4 g) in N,N-dimethylacetamide (20 mL) was stirred at 172° C. for 4.5 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatograph (silica gel/ethyl acetate and basic silica gel/hexane:ethyl acetate=9:1-85:15) and recrystallized from ethyl acetate-hexane to provide the title compound (0.97 g, yield 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.BrBr>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: O=C1CCC(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CC=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reaction time: 2 h

Procedure:
A suspension of 10.25 g of 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 880 ml of carbon tetrachloride is treated with 4.5 ml of bromine and heated to boiling while stirring for 2 hours while irradiating with a 500 W incandescent lamp. The solution is evaporated in vacuo. The residue is dissolved in 880 ml of 2 propanol and hydrogenated at room temperature and normal pressure in the presence of 1.3 g of palladium-on-carbon (5%). The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in benzene and chromatographed on 295 g of silica gel. Impurities and starting material are eluted with benzene/ethyl acetate (29:1) and the desired product is eluted with benzene/ethyl acetate (19:1). After recrystallization from benzene/ether, there is obtained 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one of melting point 214°-215°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:20][CH:21]3[CH2:38][CH:37]4[N:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([OH:42])=O)([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH:56]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57]1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:20][CH:21]3[CH2:38][CH:37]4[N:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:62][S:59]([CH:56]6[CH2:58][CH2:57]6)(=[O:61])=[O:60])=[O:42])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccncc3)nc2c1C
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccncc3)nc2c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
The acid 178 (67 mg, 0.11 mmol) and EDAC (26 mg, 0.13 mmol) were dissolved in dichloromethane (3 ml). After stirring at room temperature for 5 h the mixture was diluted with dichloromethane (10 ml) and the organic phase were washed with water and dried (sodium sulphate). The volume was then reduced to 2 ml and cyclopropyl sulphonamide (20 mg, 0.17 mmol) and DBU (36 mg, 2.3 mmol) were added. The mixture was allowed to stir over-night at room temperature and then washed using 5% aqueous citric acid. Purification by chromatography (0 to 2% methanol in dichloromethane gave the title compound (57 mg, 73%), MS (M+H)+ 704.
Reaction SMILES: O[CH:2]([C:4]1[C:12]2[O:11][CH2:10][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])[CH3:3]>[Pd].C(O)C>[CH2:2]([C:4]1[C:12]2[O:11][CH2:10][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:5]=1[CH3:31])[CH3:3]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(C)O)OC[C@@H]2c1ccc(C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Yield: 81.6 %

Procedure:
A solution of (+)-N-((3R)-7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (746 mg, 1.77 mmol) obtained in Examples 40 and 41, and 10% palladium on carbon (water content: 50%, 75 mg) in ethanol (8 mL) was refluxed with heating for 2 hours. The catalyst was removed and the reaction solution was concentrated under reduced pressure. The obtained residue was recrystallized from THF-hexane to obtain 589 mg (yield: 96%) of the title compound. Melting point: 156-157° C. [α]D20=+50.7° (c=0.46, chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a solution of 1-(4-nitrophenyl)propan-2-one (0.650 g, 3.63 mmol) in ethanol (20 mL) was added 10% palladium on carbon (0.060 g) and the mixture stirred at rt under 1 atm of H2 for 1 h. After this time, the mixture was filtered over celite, concentrated, and the residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.280 g, 51%) as an orange oil. MW=149.19. 1H NMR (CDCl3, 500 MHz) δ 7.00-6.96 (m, 2H), 6.68-6.63 (m, 2H), 3.63 (s, 2H), 3.56 (s, 2H), 2.11 (s, 3H); APCI MS m/z 150 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.CCCCCC.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:23]#[N:24])[CH3:18]>C1COCC1.O>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]([NH2:24])=[CH:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:18]
Reactant: CS(C)(=O)=O
Reactant: CCOc1cc(C#N)ccc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(N)=CS(C)(=O)=O)ccc1OC
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A slurry of dimethylsulfone (85 g, 903 mmol) in THF (480 ml) was treated with a 1.6M solution of n-butyllithium in hexane (505 ml, 808 mmol) at 0-5° C. The resulting mixture was agitated for 1 hour then a solution of 3-ethoxy-4-methoxybenzonitrile (80 g, 451 mmol) in THF (240 ml) was added at 0-5° C. The mixture was agitated at 0-5° C. for 0.5 hour, warmed to 25-30° C. over 0.5 hour and then agitated for 1 hour. Water (1.4 L) was added at 25-30° C. and the reaction mass was agitated overnight at room temperature (20-30° C.). The solid was filtered and subsequently washed with a 2:1 mixture of water:THF (200 ml), water (200 ml) and heptane (2×200 ml). The solid was dried under reduced pressure at 40-45° C. to provide the product as a white solid (102 g, 83% yield); 1H NMR (DMSO-d) δ 1.34 (t, J=7.0 Hz, 3H), 2.99 (s, 3H), 3.80 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 5.03 (s, 1H), 6.82 (s, 2H), 7.01 (d, J=8.5 Hz, 1H), 7.09-7.22 (m, 2H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH-].[K+].[CH:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[CH:14]=[O:15]>C1(C)C=CC=CC=1>[C:1]([CH2:2][CH2:3][C:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH2:9][CH:8]2[CH:14]=[O:15])#[N:4]
Reactant: C=CC#N
Reactant: O=CC1CC2C=CC1C2
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CCCC12C=CC(CC1C=O)C2
Reaction time: 6 h

Procedure:
To a solution of acrylonitrile in 50 mL of toluene was added at room temperature 2 mL of 10% aqueous solution of KOH. To this was added 5-norbornene-2-carboxaldehyde (6.1 g, 50 mmol) at ambient temperature within a period of 2 h. The resulting mixture was stirred for 6 h, quenched with 3 N aqueous HCl, extracted with toluene, dried over MgSO4. Solvent and residual starting materials were removed to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:6]=1.CN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:10]=[CH:9][C:8]=2[O:11][CH3:12])=[C:15]([CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:24][C:23]2=[O:34])[CH:16]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1ccc(CC(=O)O)cc1Oc1ccc(Br)cc1CN1C(=O)O[C@H](c2ccccc2)[C@@H]1C

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid methyl ester and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([O-:19])=[O:18]>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[N+:17]([O-:19])=[O:18])[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene was treated dropwise simultaneously with a solution of sodium hydroxide (1.24 g of 50% aqueous solution) in 5 ml of water and 2-nitrobenzoyl chloride (0.96 g). The resulting mixture was stirred at 23° C. overnight. Water was added and the mixture was extracted with ether. A second extraction was performed with methylene chloride and the combined organic extracts were dried over magnesium sulfate. Evaporation afforded 0.4 g of N'-t-butyl-N-(2-pyridinecarbonyl)-N'-(2-nitrobenzoyl)hydrazine as a yellow solid. m.p. 137°-140° C.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH2:10][OH:11])=[CH:4]2)[CH2:2]1.[H][H]>C(O)C.[Pt]=O>[CH2:1]1[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:10][OH:11])[CH2:4]2)[CH2:2]1
Reactant: [H][H]
Reactant: OCC1=CC2(CCCC1)CC2
Agent: O=[Pt]
Solvent: CCO
Product: OCC1CCCCC2(CC2)C1
Yield: 95.2 %

Procedure:
To a solution of spiro[2.6]non-4-en-5-yl-methanol (170 mg) obtained in Step 4 in ethanol (3.4 mL) was added platinum oxide (35 mg), followed by stirring the reaction mixture at room temperature under normal pressure in an atmosphere of hydrogen for 2 hours. Then, the reaction mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:7) to give spiro[2.6]non-5-yl-methanol (164 mg).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[Cl-].[Mg+2].[Cl-].[C:33](OC(C)(C)C)(=[O:38])[CH2:34][C:35]([CH3:37])=[O:36].N1C=CC=CC=1>ClCCl.CCOC(C)=O>[C:33](=[C:34]([C:35](=[O:36])[CH3:37])[C:13]([C@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])=[O:15])=[O:38]
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)C(=C=O)C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a suspension of (+)-carbobenzyloxy-D-proline (10 g, 40 mmol) in dichloromethane (250 mL) was added oxalyl chloride (6.9 mL, 80 mmol) followed by dimethyl formamide (15 μL, 0.2 mmol). The reaction mixture was then stirred for 2 h and concentrated in vacuo. The resulting acid chloride in dichloromethane (50 mL) was added to a mixture of magnesium chloride (4 g, 40 mmol) and tert-butyl acetoacetate (6.5 mL, 4 mmol) in pyridine (6.5 mL, 80 mmol) and dichloromethane (50 mL) at 0° C. and stirred for 30 min. The reaction mixture was then stirred at room temperature for 16 h and then diluted with EtOAc (25 mL). The organic layer was washed with 10% HCl solution (1×250 mL), saturated NaHCO3 solution (1×250 mL) and then brine (1×250 mL). The separated organic layer was then dried over Na2SO4 and concentrated in vacuo to afford (2R)-benzyl 2-(2-(carbonyl)-3-oxobutanoyl)pyrrolidine-1-carboxylate. LCMS: 6.51 min, calculated: 389, found (MH+): 390.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:26])[C:14]=3[NH:13][C:12]([O:11][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH3:10])=[O:27])=[CH:20][CH:21]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccc(F)cc1F
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccc(F)cc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2,4-difluoro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2,4-Difluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH:10]=[O:11].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=2[CH:10]=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)c(C=O)c1
Reactant: ClCCCCCCc1ccccc1
Product: O=Cc1ccc(OCCCCCCc2ccccc2)c(C=O)c1

Procedure:
4-(6-phenylhexyloxy)-1,3-benzenedicarboxaldehyde was prepared from 4-hydroxy-1,3-benzenedicarboxaldehyde and 6-phenylhexyl chloride using the method in Example 1 at a higher reaction temperature of 140° C.