Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[N:38][C:37]2=[CH:41][C:34]3=[N:35][N:36]2[C:13]=1[N:14]1[CH2:48][CH2:47][C:17]([CH3:49])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:46])[O:24][C:25]2[CH:26]=[C:27]([CH3:45])[CH:28]=[CH:29][C:30]=2[CH2:31][N:32]([CH:42]2[CH2:44][CH2:43]2)[CH2:33]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:39]([CH3:40])=[N:38][C:37]2=[CH:41][C:34]3=[N:35][N:36]2[C:13]=1[N:14]1[CH2:48][CH2:47][C:17]([CH3:49])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([CH3:46])[O:24][C:25]2[CH:26]=[C:27]([CH3:45])[CH:28]=[CH:29][C:30]=2[CH2:31][N:32]([CH:42]2[CH2:43][CH2:44]2)[CH2:33]3)[CH2:16][CH2:15]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)ccc1CN(C1CC1)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)O[C@@H](C)CCCCOC1(C)CCN(CC1)c1c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(nn13)CN(C1CC1)C2
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-[(20S)-11-cyclopropyl-4,16,20,26-tetramethyl-19,25-dioxa-1,5,7,8,11-pentaazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl]acetate (70 mg, 0.104 mmol) and NaOH (0.311 mL, 0.311 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then cooled to rt, purified by preparative HPLC to obtain (2S)-2-(tert-butoxy)-2-[(20S)-11-cyclopropyl-4,16,20,26-tetramethyl-19,25-dioxa-1,5,7,8,11-pentaazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl]acetic acid (42 mg, 0.065 mmol, 62.6% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.12 (d, J=7.3 Hz, 1H), 6.76 (s, 1H), 6.64 (d, J=7.7 Hz, 1H), 6.37 (s, 1H), 5.61 (s, 1H), 4.52 (br. s., 1H), 4.34 (t, J=12.3 Hz, 1H), 4.04 (d, J=14.3 Hz, 1H), 3.92 (d, J=15.0 Hz, 1H), 3.81 (d, J=14.3 Hz, 1H), 3.72 (d, J=15.0 Hz, 1H), 3.68-3.59 (m, 1H), 3.50-3.29 (m, 3H), 2.79-2.71 (m, 1H), 2.48 (s, 3H), 2.27 (s, 3H), 1.97 (br. s., 1H), 1.91 (s, 1H), 1.83 (d, J=12.8 Hz, 1H), 1.78-1.43 (m, 8H), 1.20 (d, J=5.9 Hz, 3H), 1.17 (s, 3H), 1.14 (s, 9H), 0.45 (d, J=5.5 Hz, 1H), 0.35 (d, J=4.8 Hz, 2H), 0.27 (br. s., 1H). LCMS (M+1)=648.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]3[O:21]C[O:19][C:14]3=2)[N:9]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:21])[C:14]=2[OH:19])[N:9]=1
Reactant: O=C1CC(c2ccccc2F)=Nc2ccc3c(c21)OCO3
Agent: [Pd]
Solvent: CO
Product: O=C1CC(c2ccccc2F)=Nc2ccc(O)c(O)c21
Yield: 13.7 %

Procedure:
To a solution of 19 (0.1 g, 0.35 mmol) in anhydrous MeOH (30 mL) was hydrogenated in the presence of 10% Pd/C (0.2 g) at 25±2° C. for 40 h. The catalyst was filtered off and the filtrate was evaporated. The crude was purified by column chromatography (SiO2, EtOAc: MeOH=30:1) to give 40. White solid; yield: 13.7%; mp 152-154° C.; MS (EI, 70 eV): m/z 271 (M+); IR (KBr): 1622.13 (C═O) cm−1; 1H-NMR (DMSO-d6, 200 MHz): δ 6.03 (s, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.30-7.70 (m, 6H), 9.72 (s, 1H), 11.76 (s, 1H); 13C-NMR (DMSO-d6, 50 MHz): δ 107.67, 108.57, 116.75 (d, J=21.5 Hz), 120.54, 122.67, 123.36, 125.42, 126.70, 131.22, 132.49, 134.35, 144.30, 154.29, 159.43 (d, J=248.5 Hz), 176.82; Anal. calcd for C15H10FNO3: C, 66.42; H, 3.72; N, 5.16. Found: C, 66.38; H, 3.70; N, 5.15.
Reaction SMILES: C([NH:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([O:14]C)=[O:13])(=O)C1C=CC=CC=1.C(N(CC)CC)C>Cl>[NH2:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Agent: Cl
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H](CN)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
20.08 g (0.08 mole) of methyl (2S,3R)-2-(N-benzoyl amino)methyl-3-hydroxybutyrate were dissolved in 60.8 g of 12N-hydrochloric acid solution, refluxed with application of heat for 6 hours and cooled to room temperature, so that a solid was precipitated. After the solid was filtered, the filtrate was washed twice with 100 ml of toluene. Then a water phase was concentrated to a residue in vacuo. To this was added 250 ml of acetonitrile and further, under an ice water cooling, 0.08 g (0.08 mole) of triethylamine. The total solution was stirred overnight at room temperature to yield precipitates. The precipitates were filtered, washed with 200 ml of acetonitrile and dried in vacuo, thereby obtaining 8.51 g (0.06 mole) of (2S,3R)-2-aminomethyl-3-hydroxybutyric acid. Yield was 80%. This compound corresponded to that described in the Japanese published application Hei 2-134 349 according to an 1H-NMR spectrum analysis.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:20])[CH2:18]O)[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:33][CH2:18][C@@H:17]([CH3:20])[C@@H:16]1[C@:21]2([CH3:27])[C@H:13]([C@H:12]3[C@H:24]([CH2:23][CH2:22]2)[C@:25]2([CH3:26])[C:9]([CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6][C@@H:5]2[O:4][C:1](=[O:3])[CH3:2])=[CH:10][CH2:11]3)[CH2:14][CH2:15]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A solution of 0.54 g of (20S)-1α,3β-diacetoxy-21-hydroxy-20-methyl-pregn-5-ene and 0.825 g of carbon tetrabromide in 10 ml. of ether was treated with 0.625 g of triphenylphosphine and the mixture was left at room temperature for 16 hours. After dilution with ether, insoluble material was filtered off. The filtrate was concentrated in vacuo and the residue was chromatographed on 15 g of silica gel using hexane/ether (9:1) for the elution. There was obtained 0.55 g of uniform (20S)-21-bromo-1α,3β-diacetoxy-20-methyl-pregn-5-ene in the form of a colourless powder of melting point 75°-76° C.; [α]D =-13.8° (c=0.5 in chloroform).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:16][NH2:17]>C1COCC1>[Cl:8][C:7]1[C:2]([NH:16][NH2:17])=[N:3][CH:4]=[CH:5][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2ccnc(Cl)c2Cl)cc1
Reactant: NN
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccnc(NN)c2Cl)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of 2,3-dichloro-4-p-tolylpyridine (711 mg, 3.0 mmol) in THF (5 mL) at room temperature under argon was added hydrazine (288 mg, 9.0 mmol). The reaction mixture was heated at 60° C. under argon for 5 h. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. Water (25 mL) was added to the residue while stirring. Solid precipitate was collected by filtration and further washed with water (15 mL×2). After drying in a vacuum oven under reduced pressure overnight, 692 mg of nearly pure title compound was obtained as an off-white solid. HPLC/MS: retention time=2.10 min, [M+H]+=234.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:33]=1)[C:7](=[O:32])[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)=[C:9]([CH:11]([NH:13]C(C1C=CC=CC=1C(O)=O)=O)[CH3:12])[N:10]=2.CCO.Cl>>[NH2:13][CH:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:33][N:6]2[C:7](=[O:32])[C:8]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[CH3:12]
Reactant: CC(NC(=O)c1ccccc1C(=O)O)c1nc2ccc(F)cn2c(=O)c1-c1cccc(F)c1
Agent: Cl
Solvent: CCO
Product: CC(N)c1nc2ccc(F)cn2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a suspension of 2-(1-(7-fluoro-3-(3-fluorophenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethylcarbamoyl)benzoic acid (0.2462 g, 0.548 mmol) in EtOH (5.48 mL, 0.548 mmol) was added concd. HCl (0.457 mL, 5.48 mmol), and the mixture was stirred under reflux. After 25 h, the mixture was cooled to rt. To the mixture was added ice water (50 mL). The aq acidic mixture (pH˜1.5) was washed with DCM (50 mL×2) to remove organic impurities. The aq mixture was then treated with satd aq NaHCO3 solution (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with water (50 mL×1) and brine (50 mL×1), dried over Na2SO4, filtered, and concd under reduced pressure to give 2-(1-aminoethyl)-7-fluoro-3-(3-fluorophenyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow foamy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88-8.93 (1H, m), 8.10 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.83 (1 H, dd, J=9.6, 5.7 Hz), 7.47-7.55 (1 H, m), 7.17-7.28 (3 H, m), 3.77 (1 H, q, J=6.7 Hz), 1.93 (2 H, br. s.), 1.18 (3 H, d, J=6.3 Hz); Mass Spectrum (ESI) m/e=302.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[C:5]([CH3:17])[C:4]=1[CH:18]=O.Cl.NO.[N:23]1C=CC=CC=1.C1(C)C=CC=CC=1>O.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[CH:6]=[C:5]([CH3:17])[C:4]=1[C:18]#[N:23]
Reactant: c1ccncc1
Reactant: COc1c(C=O)c(C)cc2c1C(C)(C)CCC2(C)C
Agent: Cl
Agent: NO
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C#N)c(C)cc2c1C(C)(C)CCC2(C)C

Procedure:
A mixture 1-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-carboxaldehyde (67.95 g, 0.261 mol), hydroxylamine hydrochloride (19.10 g, 0.275 mol), pyridine (21 mL) and toluene (260 mL) was heated at reflux, with removal of water via a Dean-Stark trap, for 20 h. The mixture was cooled and hexane/ethyl acetate (8:1, 100 mL) and water (250 mL) was added. The layers were separated and the aqueous layer extracted with hexane/ethyl acetate (8:1, 2×50 mL). The combined organic extracts were washed with water (2×100 mL), 2N hydrochloric acid (2×100 mL), and brine (100 mL). Evaporation of solvents and crystallization from hexane provided 1-methoxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1), (56.17 g), mp 71°-73° C., GLC purity 99%+. 1H-NMR (CDCl3) δ 1.25 and 1.36 (12H, 2s), 1.62 (4H, s), 2.43 (3H, s), 4.07 (3H, s), 6.92 (1H, s); IR (CHCl3) νmax 2950, 2200, 1600, 1540, 1460 cm-1. MS (m/e) 257, 242, 200; UV νmax (ethanol) 224 (ε=2100), 247 (ε=2800), 289 (ε=840) nm.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[CH2:8]([NH2:11])[CH2:9][NH2:10].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:7][C:5]1[N:6]=[C:2]([NH:10][CH2:9][CH2:8][NH2:11])[S:3][CH:4]=1
Reactant: NCCN
Reactant: Cc1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1csc(NCCN)n1
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-4-methylthiazole (502 mg, 2.82 mmol), ethylenediamine (15 mL, 224 mmol) and potassium carbonate (780 mg, 5.64 mmol) was heated under microwave heating at 120° C. for 30 min in a closed vial. Ethanol (200 mL) was added, the resulting mixture was filtered, the solids washed with EtOH and the combined filtrates concentrated under reduced pressure. The residue was mixed with toluene and concentrated under reduced pressure; this step was repeated two times after which 620 mg of a solid was obtained that was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:27])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:7]2[OH:26]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:3]([OH:27])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[C:8]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:7]2[OH:26]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(O)c(F)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
A mixture of 1,1-dimethylethyl N-((8-fluoro-4,7-dihydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.21 g, 0.55 mmol) in 2 mL TFA was stirred at room temperature for 30 minutes, M+1=324, M−1=322. The mixture was concentrated and triturated in ether/hexane (1:10). The solid was filtered, washed with 10 mL ether/hexane (1:10), and dried under high vacuum to give 0.17 g of the product as a yellow solid. MS (m/z)=324 (M+H)+. Calculated for C15H14FNO6 323.08.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:26]([F:39])=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][C:26]([F:39])=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(C(C)c3oc4ccc(F)cc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.2 %

Procedure:
To a solution of Example 121 (0.180 g, 0.324 mmoles) in dichloromethane (15 ml), BBr3 (1M in dichloromethane, 1.6 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as grey solid (0.045 g, 27% yield). MP: 193-196° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.74(s,1H), 8.17(s, 1H), 7.83-7.70(m, 4H), 7.63(m,1H), 7.35(t, J=8.2 Hz, 1H), 7.31(m,1H), 7.12(m,4H), 6.99(m, 2H), 6.08(q, J=6.8 Hz, 1H), 1.90(d, J=7.0 Hz, 3H). Mass: 511.87(M+).
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([C:15](=[C:26]2[CH:33]3[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:35][CH:27]2[CH2:28]4)[CH2:32]3)[O:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[CH:13][CH:14]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:1][C:9]1[CH:10]=[C:11]([C:15](=[C:26]2[CH:27]3[CH2:35][CH:31]4[CH2:30][CH:29]([CH2:34][CH:33]2[CH2:32]4)[CH2:28]3)[O:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCOc2ccccc2)=C2C3CC4CC(C3)CC2C4)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cccc(C(OCCOc2ccccc2)=C2C3CC4CC(C3)CC2C4)c1
Reaction time: 2 h

Procedure:
To a solution of 6.30 parts of alkene (55) in 100 mL of THF was added 7.0 parts of 70% mixture of tetra-n-butylammonium fluoride in 50 mL of THF over a period of 15 minutes. The reaction mixture was stirred for two hours. TLC on silica gel plate showed the formation of new product. The solvent was evaporated under reduced pressure and the oily material was dissolved in 300 mL of ethyl acetate and washed with two times with 200 mL of water. After drying over anhydrous sodium sulfate, the solvent was evaporated and the oily product was purified on silica gel column. TLC on silica gel plate of the fractions were checked and the combined organic solvent was evaporated, yield 3.75 parts. The structure of the product was confirmed on the basis of 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(-c2nc3cc(N)ccc3o2)cc1
Temperature: 53 °C

Procedure:
A 7.5-gram portion of the 2-(p-nitrophenyl)-5-nitrobenzoxazole is dissolved in 100 milliliters of 1,4-dioxane. A 10% palladium-on-carbon catalyst (2.0 grams) is added, and the mixture stirred under nitrogen. The mixture is heated to 53° C., and hydrogen gas is bubbled into the mixture for about 6.5 hours. The catalyst is then filtered off and the remaining solution added to water. The solvent and water are then evaporated off to yield 2-(p-aminophenyl)-5-aminobenzoxazole.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:25]([CH3:28])([CH3:27])[CH3:26])(=O)=O>C1(C)C=CC=CC=1>[CH3:26][Si:25]([N:9]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([C:3]#[N:2])=[CH:5][CH:6]=1)[Si:25]([CH3:28])([CH3:27])[CH3:26])([CH3:28])[CH3:27]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N(Cc1ccc(C#N)cc1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.2 %

Procedure:
About 5.20 g of 4-(aminomethyl)benzonitrile hydrochloride, 10.30 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 15.1 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 3 days to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 4-[bis(trimethylsilyl)aminomethyl]benzonitrile (4-BTMSAMBZN) as a white solid (8.12 g, 95% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.00 (doublet, 2H, aromatic protons), 6.83 (doublet, 2H, aromatic protons), 3.72 (singlet, 2H, CH2 protons), −0.06 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[SH:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:8]=1[C:9]#[N:10].C[O-].[Na+]>CO>[NH2:10][C:9]1[C:8]2[C:7](=[N:14][C:13]([CH3:15])=[CH:12][C:11]=2[CH3:16])[S:6][C:2]=1[C:3]([NH2:5])=[O:4]
Reactant: Cc1cc(C)c(C#N)c(S)n1
Reactant: NC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c2c(N)c(C(N)=O)sc2n1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
α-Bromoacetamide (388 mg, 2.81 mmol) was added to a solution of 2-mercapto-4,6-dimethyl-nicotinonitrile (420 mg, 2.56 mmol) in MeOH (25 mL) at room temperature. This was followed by addition of sodium methoxide (1.76 mL, 25% NaOMe in MeOH, 7.7 mmol). The reaction mixture was heated to reflux. Heating at reflux was continued overnight, after which time the reaction mixture was cooled and filtered. The product was dried overnight providing 450 mg (80%) of the title compound, m.p. 238-40° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=5[F:28])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: Fc1ccccc1CBr
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccccc3F)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-benzyl bromide following a procedure analogous to that described for Intermediate 7. LC (method 6): tR=1.19 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=O)=[CH:11][CH:10]=1)[CH3:8].O=S(Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a 3-neck, 2 L round bottom flask was added 173.71 g (1.0 mol, 97%) of 2-amino-2-methyl-1-propanol in 300 mL of dry methylene chloride. The flask was equipped with a magnetic stir bar and thermometer and was placed into a dry ice/acetone bath and cooled to 0° C. From a separatory funnel, a solution of 4-ethylbenzoyl chloride (168.5 g, 1.0 mol), dissolved in about 300 mL of methylene chloride was slowly added, while maintaining the reaction temperature below 5° C. The mixture was allowed to stir at room temperature overnight. Solid propanol amine-HCl was filtered off and the filter cake was washed with methylene chloride. The combined methylene chloride extracts were concentrated partially on a rotary evaporator and used directly in the next step. The intermediate amide solution generated in the first step was cooled in an ice bath and DMF (0.5 mL) was added. 125 g (1.04 mol) of SOCl2 in 50 mL of methylene chloride from a separatory funnel was added drop-wise at a controlled rate, keeping the reaction temperature at 0-5° C. The reaction was stirred at room temperature for an additional 2-3 hours. The reaction mixture was cooled in an ice bath and 25% NaOH was added to make the aqueous layer basic (pH=11-12). The mixture was transferred to a large separatory funnel, the methylene chloride layer was separated, and the aqueous layer was extracted twice with chloroform. The combined organic phases were dried and evaporated to yield 201 g of 2-(4-ethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole as a yellow viscous oil. 1H NMR (CDCl3, 300 MHz), δ (ppm): 7.8 (d, 2H), 7.2 (d, 2H), 4.088 (s, 2H), 2.68 (q, 2H), 1.375 (s, 6H), 1.24 (t, 3H).