Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.CCO.O>[C:24]1([C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]=34)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C

Procedure:
Tricyclic bromide 11 (0.2 g, 0.75 mmol) in toluene (20 mL) and EtOH (10 mL) was treated with solid Na2CO3 (0.199 g, 1.88 mmol), LiCl (0.095 g, 2.25 mmol), phenylboronic acid (0.138 g, 1.13 mmol), and water (0.50 mL). The solution was degassed and tetrakis(triphenylphosphine)palladium(0) (43 mg, 5 mol %) was added. The solution was heated at reflux for 5 h, and then cooled to ambient temperature and diluted with water (20 mL). The aqueous layer was adjusted to pH=7-8 with saturated aqueous K2CO3 and extracted with EtOAc (20 mL×3). The organic solution was washed with water and brine, and dried (Na2SO4), filtered, and concentrated. The crude product was recrystallized (CH2Cl2/MeOH/hexanes) to yield the 2-phenyltricycle as a pale-yellow solid, 183 mg (93%). mp 249-255° C. (dec); 1H NMR (CDCl3/CD4OD) δ 3.14 (m, 2H), 3.53 (m, 2H), 7.23 (t, 1H, J=7.7 Hz), 7.33 (m, 1H), 7.44 (m, 2H), 7.55 (m, 3H), 7.83 (d, 1H, J=7.7 Hz); HRMS (M+H) Calcd for C17H14N2O+H: 263.1184, Found: 263.1189; Anal. (C17H14N2O.0.8 H2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Br:10]Br>C(=S)=S>[Br:10][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[OH:9]
Reactant: BrBr
Reactant: COc1cccc(O)c1
Solvent: S=C=S
Product: COc1ccc(Br)c(O)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a mixed solution of 25 g of 3-methoxyphenol and 100 ml of carbon disulfide (CS2) was added dropwise 10.3 ml of bromine at room temperature. After stirring the mixture for 30 minutes, the solvent was removed under reduced pressure, and water was added to the residue. The reaction mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure to give 34.8 g of 2-bromo-5-methoxyphenol (yield: 85%, boiling point: 96°-98° C. (4 mmHg), colorless oily product).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]([CH3:39])[C@H:15]([C:19]([N:21]([CH3:38])[C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:12]([N:14]([CH3:39])[C@H:15]([C:19]([N:21]([CH3:38])[C@H:22]([C:35]([NH2:37])=[O:36])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([C:31]([CH3:32])([CH3:34])[CH3:33])[CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)cc1F)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccc(O)cc1F
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a solution of Boc-Tyr(2-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.21 g, 0.326 mmol) in methylene chloride (3 ml), TFA (1.5 ml) was added and stirred for 15 min. The reaction mixture was concentrated under reduced pressure, mixed with a saturated aqueous NaHCO3 solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The resultant was evaporated to remove the solvent under reduced pressure, giving the titled compound (173 mg, 82%).
Reaction SMILES: C(OC([N:8]1[CH2:38][CH2:37][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[CH:12]2[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:53][CH2:54][CH:55]1[O:59][CH2:58][CH2:57][O:56]1.[I-].[Na+].[ClH:62]>C(OCC)C>[ClH:62].[O:56]1[CH2:57][CH2:58][O:59][CH:55]1[CH2:54][CH2:53][N:8]1[CH2:9][CH2:10][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])=[CH:22][CH:23]=3)[CH:12]2[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:37][CH2:38]1
Reactant: CC(C)COc1ccc(CN2C(=O)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2Cc2ccc(F)cc2)cc1
Reactant: BrCCC1OCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COc1ccc(CN2C(=O)OC3(CCN(CCC4OCCO4)CC3)C2Cc2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
69NLS77 (300 mg, 0.57 mmol) was N-BOC deprotected by treatment with a solution of TFA (2 mL) in dichlornethane (2 mL) at rt for 1.5 h. The solvent was removed in vacuo, the residue coevaporated twice with acetonitrile and redissolved in the same solvent (10 mL). Potassium carbonate (110 mg, 0.80 mmol) and 2-(2-bromoethyl) 1,3-dioxolane (80 μL, 0.68 mmol) were added, followed by sodium iodide (102 mg, 0.68 mmol) and the mixture stirred for 3 days at 50° C. Partitioning of the mixture between water and dichloromethane, extraction of the aqueous layer twice with dichloromethane, drying of the combined organic layers over Na2SO4, filtering and evaporation of the solvent gave crude 69NLS79-II. The residue was purified by silica gel column chromatography, eluting with a stepwise gradient of 0-4% methanol in dichloromethane, affording 69NLS79-II (127 mg, 0.24 mmol) as a colorless oil. The compound was converted to its HCl form by treatment with 2M HCl in diethylether as described above for 69NLS75, giving the salt as a colorless powder.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15]([NH2:17])=[O:16])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC#N>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([CH:11]([NH:14][C:15]([NH2:17])=[O:16])[CH2:12][CH3:13])[CH2:9][CH2:10]1
Reactant: CCC(NC(N)=O)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: CCC(NC(N)=O)C1CCC(=O)CC1

Procedure:
A solution of (1-1,4-dioxaspiro[4.5]decan-8-ylpropyl)urea (as prepared in the previous step, 89 mg, 0.37 mmol, 1.00 equiv) in CH3CN (2 mL) and HCl (2M, 2 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 20 mL of aq. sodium bicarbonate (1M). The resulting solution was extracted with 2×20 ml, of dichloromethane. The organic layers were combined, dried and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]#[C:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1>C1COCC1>[F:19][CH:2]([F:1])/[CH:3]=[CH:4]/[C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CC(F)F)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(/C=C/C(F)F)CC1
Temperature: -78 °C
Reaction time: 5 h
Yield: 103.3 %

Procedure:
To a solution of tert-butyl 4-(3,3-difluoroprop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate (280 mg, 1.016 mmol) in 30 mL of anhydrous THF was added dropwise sodium dihydro-bis-(2-methoxyethoxy)aluminate (587 mg, 2.032 mmol, 70%) at −78° C. under N2. After the addition, the reaction mixture was stirred at −78° C. under N2 for 5 h. The reaction mixture was quenched by sat. NH4Cl aq., and the resulting mixture was extracted with EtOAc (50 mL, 30 mL). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo to afford 291 mg of title compound. MS (ES) M+H expected 278.15. found 178.30. 1H NMR (CHLOROFORM-d) δ: 6.29-6.08 (m, 2H), 6.01-5.84 (m, 1H), 3.98-3.84 (m, 2H), 3.20 (t, J=11.4 Hz, 2H), 1.76-1.62 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](OC)=[O:10])[CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:9][OH:10])[CH:3]=1
Reactant: COC(=O)c1cc(Br)nc(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(Br)cc(CO)n1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a cold suspension of methyl 6-bromo-2-methylpyrimidine-4-carboxylate (5.4 g, 23.3 mmol, Preparation #3) in MeOH (100 mL) was added NaBH4 (1.11 g, 29.13 mmol, Spectrochem) in small portions over a period of about 45 min at about −10° C. and stirred at the same temperature for about another 30 min. The reaction was quenched with saturated ammonium chloride solution (150 mL) and the product was extracted with EtOAc (2×200 mL). The combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure to afford (6-bromo-2-methylpyrimidin-4-yl)methanol 4.10 g (87.2%). 1H NMR (400 MHz, DMSO) δ: 7.56 (s, 1H), 5.72 (brs, 1H), 4.51 (d, J=3.6 Hz, 2H), 2.57 (s, 3H); MS m/z: 205(M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Cc1cc(Cl)ccn1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccnc(C)c2)cc1C=O
Temperature: 85 °C

Procedure:
A stirred suspension of 3-formyl-4-methoxybenzeneboronic acid (700 mg, 3.89 mmol), 4-chloro-2-picoline (494 mg, 3.89 mmol), potassium carbonate (1.45 g, 10.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (225 mg, 0.19 mmol) in 1,2-dimethoxyethane (14 mL) and water (5 mL) is degassed at RT with N2 for 15 minutes then warmed for 16 h at 85° C. The reaction mixture is then cooled to RT and 2 M HCl (15 mL) added. The aqueous layer is washed with TBME (15 mL) then basified to pH 10 with aqueous K2CO3 and extracted into EtOAc (3×50 mL); The combined organic phases are dried over Na2SO4 and the solvents removed in vacuo to give the title compound.
Reaction SMILES: [CH3:1][SH:2].[CH:3]([N:6]1[C:10](Cl)=[N:9][C:8]([OH:12])=[N:7]1)([CH3:5])[CH3:4].S([O-])(O)(=O)=O.[K+]>[OH-].[Na+]>[CH:3]([N:6]1[C:10]([S:2][CH3:1])=[N:9][C:8]([OH:12])=[N:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)n1nc(O)nc1Cl
Reactant: CS
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Product: CSc1nc(O)nn1C(C)C
Temperature: 100 °C

Procedure:
An amount of 19.6 g of methylmercaptan is added at -5°C, with stirring, to 200 ml of 5N aqueous sodium hydroxide solution. An addition is then made of 33 g of 1-isopropyl-5-chloro-3-hydroxy-1,2,4-triazole, and the mixture heated for 2 hours at 100°C. After cooling to 20°C, the solution is acidified by the addition of potassium hydrogen sulphate, and extracted with ethyl acetate. The ethyl acetate extract is dried over anhydrous magnesium sulphate; it is then concentrated in a water-jet vacuum, and the residue crystallised from a little methanol at -70°C. The obtained product is 1-isopropyl-5-methylmercapto-3-hydroxy-1,2,4-triazole with a melting point of 90°-92°C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CS(C)=O>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: Cc1ccncc1I
Reactant: O=c1[nH]ccc2ccc(C(F)(F)F)cc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1ccncc1-n1ccc2ccc(C(F)(F)F)cc2c1=O
Yield: 25.8 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-2H-isoquinolin-1-one (I-29d: 0.15 g, 0.0007 mol) was reacted with 3-iodo-4-methyl-pyridine (0.185 g, 0.8 mmol), DMSO (30 mL), copper iodide (0.026 g, 0.00014 mol), quinolin-8-ol (0.02 g, 0.14 mmol) and potassium carbonate (0.126 g, 0.9 mmol) to afford the crude product. Purification by column chromatography on silica gel (8% ethylacetate in hexane) afforded 0.055 g of the product (23.8% yield).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[ClH:18].O1CCOCC1>>[ClH:18].[NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CCCN1
Reaction time: 1 h

Procedure:
A mixture of (S)-1-tert-butyl 2-ethyl pyrrolidine-1,2-dicarboxylate (200 mg, 0.822 mmol) and HCl in 1,4-dioxane (4110 μl, 16.44 mmol) was allowed to stir for 1 hour. The reaction mixture was concentrated to give (S)-ethyl pyrrolidine-2-carboxylate hydrochloride; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.2 Hz, 3H) 2.00-2.22 (m, 3H) 2.39-2.48 (m, 1H) 3.49-3.67 (m, 2H) 4.29 (q, J=7.2 Hz, 3H) 9.09 (br s, 1H) 10.98 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:31][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.O.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:31][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Temperature: 50 °C
Yield: 97.2 %

Procedure:
Methyl 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate (5.83 g, 12.8 mmol) was dissolved in 25 mL of THF and 25 mL of water and treated with LiOH (1.35 g, mono-hydrate). The whole was heated at 50° C. for 3 h, cooled to room temperature and acidified. The resulting precipitate was filtered and washed with water. The filter cake was dried to a constant weight under vacuum to give 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (5.47 g, yield 97%). ESI-MS: 440.2. 1H NMR (DMSO-d6, 400 MHz): δ12.34 (s, 1H, NH), 7.74-7.42 (m, 7H, ArH), 6.50 (s, 1H, ═CH), 4.18 (t, J=5.2 Hz, 2H, CH2), 2.98 (t, J=5.2 Hz, 2H, CH2).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[NH:5][C:6]=1[Br:7].[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[N:5]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:6]=1[Br:7]
Reactant: Brc1nc(C2CC2)[nH]c1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1Br
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution of 4,5-dibromo-2-cyclopropyl-1H-imidazole (60 g, 226 mmol) in THF (150 mL) was added dropwise over 50 minutes under nitrogen to a stirring mixture of sodium hydride (95%, 6.3 g, 250 mmol) in dry THF (150 mL) at 0° C. The reaction mixture was stirred 30 minutes and 2-(trimethylsilyl)ethoxymethylchloride (SEMCl, 40 mL, 38 g, 226 mmol) was added dropwise over 50 minutes at 0° C. After stirring for 1 hour, the reaction was slowly quenched with water (20 mL) and added EtOAc (500 mL). The mixture was washed with water (2×750 mL) and the combined aqueous portions were back extracted with EtOAc (200 mL). The combined organic portions were washed with brine (1 L), dried (Na2SO4), and concentrated. The resulting residue was dissolved in heptane (200 mL) and the resulting solution was passed through a pad of silica gel, eluting with heptane (4×500 mL) and EtOAc-heptane (1:4, 2×250 mL) to give 4,5-dibromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (79 g, 199 mmol, 88%) as a pale yellow solid after concentration: LCMS (m/z) 394.9 (MH+), tR=1.20 minutes, 1H NMR (400 MHz, CDCl3) δ ppm −0.04-0.05 (m, 9H), 0.87-1.12 (m, 6H), 1.88-2.04 (m, 1H), 3.55-3.66 (m, 2H), 5.37 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.CC(C)([O-])C.[K+].[N:17]1([S:21]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[C:29](F)=[CH:28][C:27]=2[F:34])(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18]1.Cl>CS(C)=O>[N:17]1([S:21]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:10][CH2:9][CH:1]3[C:3]4([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH2:2]3)=[CH:28][C:27]=2[F:34])(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: OCC1CC12CCCCC2
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CC23CCCCC3)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of spiro[2.5]octan-1-ylmethanol (prepared according to Huang and Forsyth, Tetrahedron 1997, 53, 16341) (0.40 g, 2.87 mmol) in anhydrous dimethylsulfoxide (5 mL) was added potassium tert-butoxide (0.81 g, 7.24 mmol) and the reaction mixture was stirred for 30 minutes at ambient temperature. To this reaction mixture was added N-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide (0.90 g, 2.89 mmol) and stirred for 2 hours. The mixture was poured into 1 M aqueous hydrochloric acid, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 30% ethyl acetate in hexanes) to afford the title compound (0.49 g, 39%): 1H NMR (300 MHz, DMSO-d6) δ 11.81 (br s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.5 Hz, 1H), 4.35-4.31 (dd, J=10.9, 6.3 Hz, 1H), 4.04 (t, J=7.7 Hz, 5H), 2.17 (q, J=7.7 Hz, 2H), 1.77-0.94 (m, 11H), 0.57-0.55 (dd, J=8.5, 4.3 Hz, 1H), 0.30 (t, J=4.7 Hz, 1H); MS (ES−) m/z 429.20 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([N+:16]([O-])=O)=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([NH2:16])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)c1n[nH]cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1

Procedure:
4-Nitro-1H-pyrazole-3-carboxylic acid (4-fluorophenyl)-amide (15 g) was dissolved in 200 ml of ethanol, treated with 1.5 g of 10% palladium on carbon under a nitrogen atmosphere, then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate evaporated. The crude product was dissolved in acetone/water (100 ml:100 ml) and after slow evaporation of the acetone the product was collected by filtration as a brown crystalline solid (8.1 g). (LC/MS: Rt 1.58, [M+H]+ 220.95).
Reaction SMILES: [C:1](=[O:44])([O:3][CH2:4][CH2:5][O:6][C@@H:7]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:36])[NH:15][C@H:16]([CH2:24][NH:25][CH2:26]C(OCC[Si](C)(C)C)=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9]1)[NH2:2].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl>[C:1](=[O:44])([O:3][CH2:4][CH2:5][O:6][C@@H:7]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:36])[NH:15][C@H:16]([CH2:24][NH:25][CH3:26])[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9]1)[NH2:2].[C:47]([OH:49])([C:46]([F:51])([F:50])[F:45])=[O:48]
Reactant: C[Si](C)(C)CCOC(=O)CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCOC(N)=O)c2cccc(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCOC(N)=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(2-(trimethylsilyl)ethoxycarbonylmethylamino)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethyl carbamate (0.0250 g, 0.038 mmol) and trifluoroacetic acid (1 mL) in CH2Cl2 (5 mL) was stirred at rt for 3 h. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 13 min, flow rate 25 mL/min) to give 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethyl carbamate as its TFA salt (0.0205 g, 86%). LC-MS (3 min) tR=1.49 min, m/z 511, 509 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.28-7.12 (m, 4H), 4.20 (d, J=13.2 Hz, 1H), 4.11-3.99 (m, 3H), 3.95 (d, J=8.8 Hz, 1H), 3.87 (d, J=13.2 Hz, 1H), 3.40-3.28 (m, 2H), 2.96 (dd, J=12.6, 3.2 Hz, 1H), 2.84 (dd, J=12.6, 10.2 Hz, 1H), 2.73-2.63 (m, 2H), 2.61 (s, 3H), 1.71-0.75 (m, 18H).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([NH2:12])[C:6]([NH2:11])=[CH:7][C:8]=1OC.S1C=CC=C1[C:18](=O)[C:19](O)=[O:20]>>[NH:12]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:3][CH:4]=2)[N:11]=[CH:18][C:19]1=[O:20]
Reactant: COc1cc(N)c(N)cc1OC
Reactant: O=C(O)C(=O)c1cccs1
Product: O=c1cnc2ccccc2[nH]1

Procedure:
The quinoxalin-2-one of the present example is prepared with 4,5-Dimethoxy-benzene-1,2-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6,7-Methoxy-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=CC=1.[CH2:20]([O:27][C:28]1[N:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>C(COC)OC.O>[CH2:20]([O:27][C:28]1[C:29]([CH2:30][C:16]#[N:17])=[CH:32][CH:33]=[CH:34][N:35]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: O=Cc1cccnc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: N#CCc1cccnc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of potassium t-butoxide (4.52 g) and dimethoxyethane (20 mL) was added a solution (20 mL) of toluenesulfonylmethylisocyanide (4.12 g) in dimethoxyethane at −78° C. Further, a solution (20 mL) of 2-(benzyloxy)nicotinaldehyde (4.12 g) in dimethoxyethane was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 1 hr. Methanol (20 mL) was added to the reaction mixture at room temperature and the mixture was heated under reflux for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(2-benzyloxy-3-pyridyl)acetonitrile as an oil from a fraction eluted with ethyl acetate-hexane (1:8, v/v).