Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][CH2:5][N:4]([CH3:7])[CH:3]=1.C([Li])CCC.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15]>CCOCC>[CH3:7][N:4]1[CH:3]=[C:2]([Sn:14]([CH3:16])([CH3:15])[CH3:13])[S:6][CH2:5]1
Reactant: C[Sn](C)(C)Cl
Reactant: CN1C=C(Br)SC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1C=C([Sn](C)(C)C)SC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.2 %

Procedure:
A solution of 4.45 g 5-bromo-3-methylthiazole in 50 ml dry ether was cooled to -° C. and treated dropwise over 10 min. with butyllithium (10.5 ml, 26.25 mmol). The mixture was stirred at -° C. for 15 min., and a solution of 5.20 g trimethyltin chloride in 20 ml ether was added dropwise over 10 min. The reaction mixture was allowed to warm to room temperature, stirred overnight, and then washed with water. The ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 6.60 g 3-methyl-5-trimethylstannylthiazole as a light-brown liquid used directly in the next reaction.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:25]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)=[CH:24][N:23]([CH3:32])[N:22]=4)=[CH:17][CH:16]=3)=[N:10]2)=[CH:5][CH:4]=1.ClCC1C=CC2C(=CC=C([F:45])C=2)N=1>>[ClH:2].[F:45][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:3]=1)[N:10]=[C:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:24][N:23]([CH3:32])[N:22]=3)=[CH:17][CH:16]=1)[CH:8]=[CH:7]2
Reactant: Fc1ccc2nc(CCl)ccc2c1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccc(Cl)cc4n3)cc2)n1
Agent: Cl
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4cc(F)ccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 7-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline hydrogen chloride but substituting 2-chloromethyl-6-fluoro-quinoline provided the title compound. 1H NMR (400 MHz, DMSO) δ 8.67 (d, J=6.6 Hz, 2H), 8.55 (s, 1 H), 8.42 (d, J=8.3, 1H), 8.04 (m, 1H), 7.82 (m, 1H), 7.71 (m, 4H), 7.36 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7, 2H), 5.37 (s, 2H), 3.91 (s, 3 H); MS: (M+H m/z=411.2).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].Cl[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=1.O>CN(C)C=O>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24][C:23]=1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:4]2[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2]([O:1][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][N:39]=3)=[N:3]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(Oc3ccc(C(F)(F)F)cn3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.00 g) in N,N-dimethylformamide (80 ml), sodium hydride (60%, oily, 100 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. 2-Chloro-5-trifluoromethylpyridine (0.45 g) was added to the reaction mixture, which was stirred at 90° C. for two hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (10 ml) was stirred at room temperature overnight, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(5-trifluoromethyl-2-pyridyloxy)-1H-pyrazol-4-yl]propionic acid was obtained (960 mg, yield: 76%). This was recrystallized from ethyl acetate-hexane. Melting point: 107–108° C.
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:2][C:3](=[O:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COc1cccc(O)c1
Reactant: CC(C)(C)CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(OCC(=O)CC(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
A stirred solution of the product from Step B (1.626 grams) in dry DMF (18 mL) was combined with 3-methoxyphenol (1.256 grams) and cesium carbonate (3.292 grams). The mixture was stirred for 2.5 hours. The reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Concentration furnished an oil from which the title compound was isolated by chromatography over silica gel (4:1 hex/ethyl acetate).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+:14].[Na+]>O.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+:14].[Na+:14]
Reactant: O=C([O-])C1C2C=CC(C2)C1C(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: O=C([O-])C1C2CCC(C2)C1C(=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of disodium bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (10.0 g, from example 3) in water (100 g) was added 0.5 g palladium on activated carbon (5 wt %). The mixture was transferred into a Parr reactor and was subjected to hydrogenation (50 psi, room temperature) for 8 hours. The activated carbon was filtered out. Water is removed in vacuo at 75° C. The resulting product was dried and milled (m.p >300° C.).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:48])[C@H:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40]CC2C=CC=CC=2)=[CH:36][CH:35]=1)[CH2:14][C@H:15]([OH:32])[C@@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.C1COCC1.[Pd]>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:48])[C@H:13]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[CH2:14][C@H:15]([OH:32])[C@@H:16]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
The product of Step J, 85 mg was dissolved in 10 mL of methanol and 10 mL of THF, and to it was added 0.10 g of 10% palladium on carbon. The mixture was stirred under an atmosphere of hydrogen for 48 hours at room temperature, then filtered and concentrated to dryness. The residue was dissolved in 10 mL of hot ethanol and 20 mL water was added. On cooling the white solid precipitate was collected and dried under vacuum over P2O5. The yield was 72 mg (98% yield) of pure product: mp 218°-219° C. (effervesces, sinters at 215) elemental analysis, Calc'd for C33H40N2O6 : (560.696): C, 70.69; H, 7.19; N, 5.00; Found: C, 70.62; H, 7.39; N, 4.79.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:27])[C:23]3[C:24]4[N:15]([C:16](=[O:26])[CH:17]=[N:18][C:19]=4[CH:20]=[CH:21][C:22]=3[F:25])[CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CN(C)C=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]2[N:18]=[CH:17][C:16](=[O:26])[N:15]3[CH2:14][C:13]([CH2:12][N:28]4[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]4)([OH:27])[C:23]=1[C:24]=23
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)cnc4ccc(F)c2c43)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)cnc4ccc(F)c2c43)CC1
Temperature: 50 °C

Procedure:
A mixture of (7-fluoro-6-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl 4-methylbenzenesulfonate (3.64 g, 9.3 mmol) (for a preparation, see Example 9(f)), 1,1-dimethylethyl 4-piperidinylcarbamate (2.0 g, 10.2 mmol) and sodium carbonate (2.9 g, 27.9 mmol) in ethanol (110 mL) and dimethylformamide (10 mL) was heated at 50° C. for 6 h. The mixture was evaporated to remove ethanol and the residue was partitioned between dichloromethane and half-saturated brine (200 mL each).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([N:14]2[CH2:19][CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C@@H:7]([C:27]([OH:29])=[O:28])[CH2:6]1)=[O:4]>O1CCCC1.C(O)C.[Pd]>[CH3:1][N:2]([CH3:30])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)(=[O:13])=[O:12])[C@@H:7]([C:27]([OH:29])=[O:28])[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CCN(S(=O)(=O)N2CC=C(c3ccc(F)cc3)CC2)[C@@H](C(=O)O)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)N1CCN(S(=O)(=O)N2CCC(c3ccc(F)cc3)CC2)[C@@H](C(=O)O)C1
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (1.39 g, 3.16 mmol) [prepared as described in Example 28, Steps 1-4] and 10% Pd/C (0.7g) in 10 % tetrahydrofuran/ethanol (45 ml) was stirred under an atmosphere of hydrogen (1 atm) overnight. The reaction mixture was filtered through Celite with excess ethanol and the filtrate was concentrated in vacuo to give 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (88%) as a white solid. This material was converted to N-hydroxy-4-dimethylaminocarbonyl-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide by following the procedure described in Example 28, Step 5 above.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:4]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(#N)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:6]=[C:5]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:4]=1
Reactant: COc1cc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(S(C)(=O)=O)n1
Reactant: C1COCCN1
Solvent: CC#N
Product: COc1cc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Temperature: 100 °C

Procedure:
Compound 19 (150 mg, 0.405 mmol) was dissolved in acetonitrile (2 mL) and morpholine (0.282 mL, 3.24 mmol) was added, The solution was sealed and heated to 100° C. for 18 h. The solution was concentrated and the residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound as a colorless oil. 1H NMR (CDCl3) δ 5.13 (s, 1H), 4.52-4.51 (m, 1H), 3.82 (s, 3H), 3.72 (s, 8H), 3.62-3.59 (m, 2H), 3.14-3.10 (m, 2H), 1.94 (m, 1H), 1.72-1.70 (m, 1H), 1.55-1.53 (m, 2H), 1.43 (s, 9H); LCMS 2.02 min, 394 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.CS(O[CH2:13][C:14]1[S:15][C:16]2[CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][C:21]=2[N:22]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[N:36]1([CH2:13][C:14]2[S:15][C:16]3[CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][C:21]=3[N:22]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(COS(C)(=O)=O)sc2C1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2nc(CN3CCCCC3)sc2C1
Temperature: 25 °C
Yield: 30 %

Procedure:
To a toluene solution (14 ml) of tert-butyl 2-((methylsulfonyloxy)methyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (2.01 mmol) was added potassium carbonate (10 mmol) and piperidine (1.1 eq.) and the resulting reaction mixture was refluxed for 16 h. It was cooled to room temperature, diluted with ethyl acetate and the organic layer was washed successively with water and brine. After drying over sodium sulfate, the organic layer was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica). Yield: 30%.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:46][C:47]1[C:55]2[CH2:54][CH2:53][CH2:52][CH2:51][C:50]=2[N:49]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:48]=1>CN(C=O)C.C1COCC1>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH:3]1[CH2:46][C:47]1[C:55]2[CH2:54][CH2:53][CH2:52][CH2:51][C:50]=2[N:49]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:48]=1
Reactant: BrCc1nn(Cc2ccccc2)c2c1CCCC2
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4c3CCCC4)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 71.3 %

Procedure:
To a stirring solution of 164 mg (0.36 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of DMF at 0° C. is added 0.430 mL (0.78 mmol, 1.2 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and a solution of 120 mg (0.39 mmol, 1.1 equiv.) of 3-Bromomethyl-4,5,6,7-tetrahydro-1-benzyl-1H-indazole in 2 mL of DMF is added. The resulting solution is stirred for 3 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 175 mg of the title compound as a white solid: mp 173°-176° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-6.84 (m, 18H), 5.02 (s, 2H), 4.99 (m, 1H), 4.22 (s, br, 2H), 4.10 (dd, 1H, J=5.3, 8.7), 3.823 (s, 3H), 3.36 (dd, 1H, J=8.6, 15.6), 3.09 (dd, 1H, J=5.3, 15.6), 2.54-2.38 (m, 4H), 1.67 (m, 4H), 1.04 (d, 6H, J=6.6); low resolution MS (FAB)m/e 682 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C(O)C.Cl.[N:17]([O-])=[O:18].[Na+]>O>[C:1]([C:5]1[CH:10]=[C:9]([N:17]=[O:18])[C:8]([CH3:11])=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)c(C(C)(C)C)cc1N=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of 2-(tert-butyl)-5-methylphenol (32.9 g, 0.2 mol) in water:ethanol (300 ml, 2:1) was added concentrated hydrochloric acid (20 ml, 0.24 mol) and then cooled to 0° C. To the solution was added dropwise a solution of sodium nitrite (14.5 g, 0.21 mol) in water (40 ml) over 30 minutes. After completing the dropwise addition, the mixture was stirred at the same temperature for 2 hours. The precipitated crystals were collected by a filtration, and washed with a cold water. The resultant crystal was dissolved in an ethyl acetate:THF (9:1) solution, washed with saturated brine, dried over sodium sulfate, and purified by silica gel column chromatography on a small amount of silica gel which was eluted with ethyl acetate. After the solvent was removed under reduced pressure, the residue was suspended in hexane and the crystals were collected by filtration to obtain 31.4 g of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH:12]1([CH2:17][NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:2]([NH:18][CH2:17][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: NCC1CCCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCCC1)OCc1ccccc1
Reaction time: 8 h
Yield: 121.7 %

Procedure:
Benzyl chloroformate (0.919 g, 5.38 mmol) was added to a solution of cyclopentylmethylamine (0.445 g, 4.49 mmol) and DIEA (1.74 g, 13.5 mmol) in 50 mL of CH2Cl2 and the mixture was strried overnight at R.T. The mixture was concentrated in vacuo and the residue was taken up in EtOAc, washed with water, sat. aq. NaHCO3, brine, dried over MgSO4 and concentrated to give the crude N-Cbz-cyclopentylmethylamine (1.275 g) which was used without further purification. 1H NMR consistent with structure.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Cl[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1(C1C=CC=CC=1)[OH:16]>C1C=CC=CC=1>[C:2]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:1]=[CH:8][CH:7]=[CH:6][CH:15]=1
Reactant: CC[Mg]Br
Reactant: OC1(c2ccccc2)c2ccccc2CCC1Cl
Solvent: c1ccccc1
Product: O=C1c2ccccc2CCC1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 187.8 %

Procedure:
Step C Add ethylmagnesium bromide (1.76 mL, 5.27 mmol, M in) dropwise to a 0° C. solution of 2-chloro-1-phenyl-1,2,3,4-tetrahydronaphth-1-ol (1.36 g, 5.27 mmol) in dry benzene (20 mL). Stir the solution at 0° C. for 30 min and heat to reflux for 5 hours. Cool the mixture to room temperature and quench with saturated NH4Cl (aqueous). Extract with ether, combine the ethereal extracts, wash with water and brine, dry over Na2SO4 and concentrate to provide 1.1 g (94%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[CH:5]=[C:4]([C:10]#[N:11])[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([NH:9][NH:8][C:6]1[CH:5]=[C:4]([C:10]#[N:11])[CH:3]=[C:2]([Cl:1])[N:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: N#Cc1cc(Cl)nc(NN)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NNc1cc(C#N)cc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 5.0 g of 6-chloro-2-hydrazinopyridine-4-carbonitrile in 50 ml of pyridine was cooled to 0° C. in an ice bath and 3.1 g of acetyl chloride was added dropwise over a 10 minute period. The mixture became homogeneous after the addition and it was allowed to warm to ambient temperature. After 2 hours, the reaction mixture was poured into 180 ml of water and the precipitate which formed was separated by filtration and dried to give N-acetyl-N'-(6-chloro-4-cyano-2-pyridyl)hydrazine which was purified by recrystallization from ethanol.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[OH:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CO[Si](C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (2.3 mL, 18.4 mmol) was added dropwise to a solution of methyl 4-(hydroxymethyl)benzoate (2.0 g, 12.0 mmol) and triethylamine (3.3 mL, 23.7 mmol) in anhydrous THF (80 ml) cooled to 0° C. A precipitate formed and the stirring was continued at 0° C. for 1 h. The mixture was diluted with hexanes (50 mL) and precipitates eliminated by vacuum filtration through a sintered funnel. Volatiles were removed by rotary evaporation. The residue was purified by flash chromatography (DCM:Hex 1:1+1% TEA) through a short silica column providing methyl 4-[(trimethylsiloxy)methyl]benzoate as a clear liquid in a yield of 2.5 g (87%). 1H-NMR (500 MHz, CDCl3): δ=0.16 ppm (s, 9H), 3.90 ppm (s, 3H), 4.74 ppm (s, 2H), 7.38 ppm (d, J=8.0 Hz, 2H), 8.00 ppm (d, J=8.0 Hz, 2H); 13C-NMR (500 MHz, CDCl3): δ=−0.41, 52.09, 64.12, 126.08, 128.90, 129.68, 146.39, 167.10 ppm. HRMS [+Scan]; calculated m/z for C12H19O3Si 239.1098; observed mass: 239.1095.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:28])[C:25]=1[CH2:26][OH:27]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:28])[C:25]=1[CH2:26][O:27][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCc1c(Cl)cncc1Cl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1cncc(Cl)c1COC1CCCCO1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
Dihydropyrane (3.01 mL, 33.2 mmol) and p-toluenesulfonic acid monohydrate (5.06 g, 26.6 mmol) were added to a stirred solution of (3,5-dichloro-pyridin-4-yl)-methanol (1.97 g, 11.06 mmol) in DCM (40 mL). After stirring for 1 d at 40° C. the solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and saturated NaHCO3 solution (50 mL). After extraction of the aqueous layer with DCM (2×50 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with mixtures of hexane and EA) to give the title compound. MS (m/z): 261.9 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:25]([O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:13][CH2:12]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(CN2CCC(O)CC2)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1)c1ccccc1
Yield: 57.7 %

Procedure:
0.5 g (0.00212 mol) of 1-(3-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.295 ml (0.00254 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.416 g (58%) of 1-(3-nitro-benzyl)-piperidin-4-yl benzoate was obtained as yellow crystals; m.p. 54°-55°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH:16][C:17](=[O:19])[CH3:18].[C:20](Cl)(=[O:25])[CH2:21][C:22](Cl)=[O:23]>O1CCCC1>[C:17]([N:16]1[C:22](=[O:23])[CH2:21][C:20](=[O:25])[N:15]1[C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])[C:6]([CH3:8])=[CH:7][C:2]=1[F:1])(=[O:19])[CH3:18]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CC(=O)NNc1cc(SCC(F)(F)F)c(C)cc1F
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)CC(=O)N1c1cc(SCC(F)(F)F)c(C)cc1F
Yield: 70.9 %

Procedure:
2.0 g of N′-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}acetohydrazide was dissolved in 100 mL of tetrahydrofuran, 0.95 g of malonyl chloride was added under cooling with ice, stirring was carried out under cooling with ice for one hour, and then stirring was carried out under reflux with heating for 5 hours. Then, the solvent was distilled off under reduced pressure, and the obtained crystals were washed with isopropyl ether to obtain 1.74 g of 1-acetyl-2-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}pyrazolidine-3,5-dione.