Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[N:23]=[CH:22][C:21]2[NH:20][CH2:19][C@@H:18]3[CH2:24][O:25][CH2:26][CH2:27][N:17]3[C:16]=2[N:15]=1.CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O.O>[Cl:13][C:14]1[N:23]=[CH:22][C:21]2[N:20]([CH2:9][C:8]3[CH:11]=[CH:12][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[CH2:19][C@@H:18]3[CH2:24][O:25][CH2:26][CH2:27][N:17]3[C:16]=2[N:15]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)cc1
Yield: 32.1 %

Procedure:
4-Methylsulphonylbenzyl bromide (121 mg, 0.485 mmol) was added to a mixture of (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 100 mg, 0.441 mmol) and potassium tert-butoxide (59.4 mg, 0.529 mmol) in DMSO (2206 μL) at room temperature. The resultant mixture was stirred overnight at room temperature and subsequently diluted with EtOAc and water. The mixture was extracted twice with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, eluting with 0-10% MeOH/CHCl3 gradient) to afford the title compound as an off-white solid (55.9 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ 2.94-3.06 (m, 1 H), 3.08-3.29 (m, 5 H), 3.35-3.52 (m, 2 H), 3.67-3.76 (m, 1 H), 3.86-4.01 (m, 2 H), 4.25 (dd, J=13.64, 1.77 Hz, 1 H), 4.55 (s, 2 H), 7.30 (s, 1 H), 7.57 (d, J=8.34 Hz, 2 H), 7.87-7.92 (m, 2 H). ESI-MS m/z [M+H]+ calc'd for C17H19ClN4O3S, 395.09; found 395.2.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[F:11].[C:12]([O:16][C:17]([NH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][C@@H:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(F)c1CN1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Bromomethyl)-1-fluoro-3-methoxybenzene (3.19 g, 14.57 mmol), (R)-3-(tert-butoxycarbonylamino)piperidine (3.0 g, 12.67 mmol), and K2CO3 (2.63 g, 19.01 mmol) were taken up in DMF (25 mL) in a 50 mL flask. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL, ×2), dried over MgSO4, filtered, and the solvent evaporated in vacuo. The residue was purified by flash chromatography (6-50% EtOAc/hexanes) to give (R)-tert-butyl 1-(2-fluoro-6-methoxybenzyl)piperidin-3-ylcarbamate. MS ESI calc'd. For C18H22FN2O3 [M+1]+ 339. found 339.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15][N:14]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:30][CH:31](Br)[CH3:32].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][N:17]([CH2:32][CH2:31][Br:30])[CH2:16][CH2:15][N:14]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Br)Br
Reactant: O=C(OCc1ccccc1)N1CCNCCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(OCc1ccccc1)N1CCN(CCBr)CCN(C(=O)OCc2ccccc2)CC1

Procedure:
From N,N′-bis(benzyloxycarbonyl)-1,4,7-triazacyclononane (1.3.13.9), dibromoethane and potassium carbonate.
Reaction SMILES: C(O[CH:4]([S:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:5])C.O[N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18].C1C[O:22][CH2:21][CH2:20]1>>[C:16]1(=[O:17])[N:12]([O:10][C:8](=[O:9])[CH2:7][S:6][CH2:4][CH2:5][O:22][CH2:21][CH3:20])[C:13](=[O:18])[CH2:14][CH2:15]1
Reactant: O=C1CCC(=O)N1O
Reactant: CCOC(C)SCC(=O)O
Reactant: C1CCOC1
Product: CCOCCSCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The S-(1-ethoxyethyl)mercaptoacetic acid (5.76 g, 35.1 mmol) is combined with N-hydroxysuccinimide (4.85 g, 42.1 mmol) in 100 mL of anhydrous THF. To this is added a solution of 1,3-dicycloherylcarbodiimide (8.70 g, 42.1 mmol) in 65 mL of anhydrous THF. The mixture is stirred at room temperature for 2 hours, or until TLC analysis indicates complete formation of the succinimidyl ester. The mixture is then filtered, and the filtrate is concentrated in vacuo to a viscous residue. The residue is dissolved in ethyl acetate, washed with water, brine, and dried (MgSO4). Removal of the solvent leaves the crude succinimidyl ester as an oil, which is further purified by flash chromatography on silica gel, using ethyl acetate:hexanes as the column eluant, to give 5.1 g of S-1-ethoxyethylmercaptoacetic acid succinimidyl ester 8 as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:16][C:17]1[NH:18][CH:19]=[C:20]([CH:22]=O)[N:21]=1.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=[O:26])C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][C:17]1[N:21]2[C:24](=[O:26])[N:1]([CH2:2][CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:22][C:20]2=[CH:19][N:18]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Cc1nc(C=O)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ncc2n1C(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)C2
Yield: 60.7 %

Procedure:
To a solution of tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate (K. Ito et al., Eur. J. Med. Chem., 34, 977 (1999); 3.7 g), 2-methylimidazole-4-carbaldehyde (1.9 g) and acetic acid (1 ml) in 1,2-dichloroethane (100 ml) was added sodium triacetoxyborohydride (5.6 g), and mixed at room temperature for 15 hours. pH of the aqueous layer was adjusted to about 12 by adding a 1 N aqueous sodium hydroxide solution to the reaction solution, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in dichloromethane (100 ml), DBU (2.6 ml) and N,N′-carbonyldiimidazole (2.8 g) were added thereto, and mixed at room temperature for 15 hours. The reaction mixture was diluted with water and chloroform and the organic layer was collected by separation, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate:ethanol=5:1) to obtain the title compound as a yellow oil (3.5 g, 59%).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].O([Si](C)(C)C)[K:20]>C1COCC1>[C:1]([NH:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:8]([O-:10])=[O:9])([CH3:4])([CH3:2])[CH3:3].[K+:20]
Reactant: COC(=O)C(CNC(C)(C)C)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Product: CC(C)(C)NCC(C(=O)[O-])c1ccc(Cl)cc1
Product: [K+]
Reaction time: 18 h
Yield: 97.2 %

Procedure:
A solution of methyl 3-(tert-butylamino)-2-(4-chlorophenyl)propanoate (1.00 g, 3.71 mmol) in THF (15 mL) was treated with KOTMS (555 mg, 3.89 mmol) at room temperature. The reaction was allowed to stir 18 hours to completion, and the mixture was concentrated in vacuo. The residue was placed under high vacuum for three hours to afford the near-pure potassium 3-(tert-butylamino)-2-(4-chlorophenyl)propanoate (1.06 g, 97%) as a white solid. This material was used without purification. LCMS (APCI+) m/z 256.0 [M+H]+.
Reaction SMILES: [C:1](#N)C.C1OCCOCCOCCOCCOCCOC1.CI.[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:37])[CH2:30][C:31]([CH3:36])([CH3:35])[O:32]2)=[C:27]([CH3:38])[CH:26]=1>[K]>[CH3:1][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:37])[CH2:30][C:31]([CH3:35])([CH3:36])[O:32]2)=[C:27]([CH3:38])[CH:26]=1
Reactant: Cc1cc(O)cc2c1C(=O)CC(C)(C)O2
Reactant: CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CI
Product: COc1cc(C)c2c(c1)OC(C)(C)CC2=O
Yield: 85 %

Procedure:
In 50 ml of acetonitrile 4.9 g (20 millimoles) of the potassium salt of 7-hydroxy-2,2,5-trimethyl-4-chromanone are dissolved and the solution is stirred in the presence of 0.5 g (2 millimoles) of 18-Crown-6 at room temperature for 30 minutes. To the mixture 4.25 g (1.9 ml, 30 millimoles) of methyl iodide are added and the reaction mixture is stirred for a further hour. The inorganic salt is filtered off and the solvent is removed. The residue is taken up in chloroform, washed twice with 50 ml of water each, dried over sodium sulfate and evaporated. The product is crystallized from 90% ethanol. Thus 3.75 g of the desired compound are obtained, yield 85%. Mp.: 86°-88° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:17])[CH2:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13].ClO[N:20]=[CH:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]>CCO.CCOC(C)=O>[CH3:8][O:9][C:10]([C:11]1[C:21]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])=[N:20][O:13][C:12]=1[CH:14]1[CH2:16][CH2:15]1)=[O:17]
Reactant: ClON=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CC(=O)C1CC1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
Triethylamine (1.82 L, 12.84 mol) is added to 3-cyclopropyl-3-oxo-propionic acid methyl ester (913 g, 6.42 mol) and the mixture is stirred at room temperature for 30 minutes. Then, the mixture is cooled to about 10° C. and a suspension of 2,6-dichloro-benzaldehyde chloro-oxime (1440.9 g, 6.42 mol) in EtOH (3.2 L) is added slowly (the internal temperature does not exceed 24° C.). After the addition, the reaction is stirred overnight at room temperature. The reaction is diluted with EtOAc (5.3 L) and washed with water (1.7 L). The layers are separated and the aqueous layer is extracted with EtOAc (3 L). The combined organics are washed with brine, dried over Na2SO4 (anhyd), filtered and concentrated to about 10% of its total volume. The precipitate formed is filtered, triturated with ether (2 L) and dried under vacuum to obtain title compound (1275.36 g, 64% yield) as a white solid. MS (m/e): 312 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[F:24][C:25]1[C:26]([O:35][CH3:36])=[CH:27][C:28]([CH3:34])=[C:29](B(O)O)[CH:30]=1>>[F:24][C:25]1[C:26]([O:35][CH3:36])=[CH:27][C:28]([CH3:34])=[C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:30]=1
Reactant: COc1cc(C)c(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1cc(C)c(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)cc1F

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and corresponding 5-fluoro-4-methoxy-2-methylphenyl boronic acid (184 mg, 1.0 mmol) to afford after chromatographic purification the title compound (130 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ 6.94 (d, 1H, J=12.5 Hz), 6.84 (s, 1H), 6.79-6.82 (m, 2H), 4.02-4.22 (m, 1H), 3.90 (s, 3H), 3.82-3.92 (m, 1H), 3.64-3.74 (m, 1H), 3.24-3.54 (m, 4H), 2.86-3.22 (m, 3H), 2.22 (s, 3H), 1.82-1.94 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 439 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:12][CH3:13])=[N:8][NH:9][C:10]=1[OH:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH3:32])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:12][CH3:13])=[N:8][NH:9][C:10]=1[O:11][CH:21]([CH3:32])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CC)n[nH]c1O
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CC)n[nH]c1OC(C)C(=O)c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-ethyl-5-hydroxy-1H-pyrazole-4-carboxylic acid ethyl ester (1.5 g, 8.14 mmol) in DMF (10 ml) is added K2CO3 (1.15 g, 8.14 mmol). The mixture is heated to 50° C. and treated with a solution of 2-bromo-1-(2,4-dichloro-phenyl)-propan-1-one (Intermediate AA) (2.53 g, 8.96 mmol) in DMF (10 ml). Stirring continues at 50° C. for 1 hour and after cooling to RT, the reaction mixture is poured into water (300 ml, pre-cooled to 10-15° C.) which is subsequently allowed to reach ambient temperature over 3 h (with stirring). The resulting suspension is filtered, washed with water and the solid dried in vacuo overnight. The resultant crude product is triturated in diethyl ether (approx. 15 ml) for 20 mins. then dried in vacuo to yield 5-[2-(2,4-dichloro-phenyl)-1-methyl-2-oxo-ethoxy]-3-ethyl-1H-pyrazole-4-carboxylic acid ethyl ester: yield: MS: m/z 385.13 [M+H]+
Reaction SMILES: C[O:2][C:3]1[C:4]([OH:22])=[CH:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:18]([C:19]=2[CH:20]=1)[CH2:17][CH2:16][C@@:14]1([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]1[OH:21].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)C>C(O)C.O>[CH3:15][C@:14]12[CH2:16][CH2:17][C@H:18]3[C@@H:9]([CH2:8][CH2:7][C:6]4[CH:5]=[C:4]([OH:22])[C:3]([OH:2])=[CH:20][C:19]=43)[C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[OH:21]
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: C[C@]12CC[C@@H]3c4cc(O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C

Procedure:
0.70 g. of 2-methoxy-1,3,5 (10)-estratriene-3,17β-diol is heated under reflux and nitrogen purging in 10 ml. of toluene with 18 ml. of diisobutylaluminum hydride (20% in toluene) for 22 hours. The reaction mixture is cooled to about 0° C. and then decomposed with 5 ml. of ethanol and then with 5 ml. of ethanol-water mixture (1:1). The mixture is further worked up as set forth in Example 3. After purification from methanol, 0.45 g. of 1,3,5(10)-estratriene-2,3,17β-triol is obtained; m.p. 181°-183° C.; ε286 = 3420.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](OCC)(=O)[CH3:13].CCCCCC>C(O)C.S(=O)(=O)(O)O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH2:12][CH3:13])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1ccc(C)c(I)c1
Yield: 95 %

Procedure:
To a solution of 3-iodo-4-methylbenzoic acid (1.5 g, 5.7 mmol) in 25 ml of ethanol was dropped in 0.5 ml of concentrated sulfuric acid. The reaction was refluxed overnight. TLC (Ethyl Acetate/Hexane 1:10) indicated the completion of the esterification. The extra ethanol was evaporated and the residue was dissolved in 30 ml of dichloromethane, which was washed with water (10 ml) and brine (10 ml), dried, and evaporated to a thick oil. A white solid was obtained after drying under vacuo (1.56 g, in 95% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:25][CH2:24]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(F)cc2[N+](=O)[O-])CC1
Yield: 97 %

Procedure:
Method 1 was followed using 2,5-difluoronitrobenzene (1.0 eq), 4-(N-Boc-amino) piperidine (1.4 eq), and TEA (2.0 eq) at 55° C. overnight yielding tert-butyl 1-(4-fluoro-2-nitrophenyl)piperidin-4-ylcarbamate (97%). LCMS (m/z): 340.1 (MH+); LC Rt=3.28 min.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:28])([CH2:26][OH:27])[CH2:24]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1.CCOCC.O>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1([CH3:28])[CH2:26][O:27][CH2:24]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(CO)(CO)CCCCCCCCCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(CCCCCCCCCOCc2ccccc2)COC1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
n-Butyllithium (2.6 M solution in hexane, 0.295 ml, 0.767 mmol) was added to a solution of 2-(9-benzyloxy-nonyl)-2-methyl-propane-1,3-diol (221 mg, 0.686 mmol) in THF (5.1 ml) at 0° C. over three minutes, and the mixture was then stirred at the same temperature for 30 minutes. A solution of TsCl (138 mg, 0.723 mmol) in THF (0.91 ml) was added to the reaction solution at 0° C. over eight minutes, and the mixture was then stirred at the same temperature for one hour. n-Butyllithium (2.6 M solution in hexane, 0.295 ml, 0.767 mmol) was added dropwise to the reaction mixture at 0° C., and the mixture was then stirred at 60° C. for six hours. The reaction mixture was diluted with ether and water was then added, followed by extraction with ether. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give 3-(9-benzyloxy-nonyl)-3-methyl-oxetane (188 mg, 90%).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Si:14]([O:21][C@H:22]1[CH2:26][CH2:25][O:24][C:23]1([OH:28])[CH3:27])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O>[Si:14]([O:21][C@@H:22]([CH2:26][CH2:25][O:24][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[C:23](=[O:28])[CH3:27])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC1(O)OCC[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
Imidazole (125 mg, 1.84 mmol, 2.2 equiv) and tert-butyl-dimethylsilyl chloride (139 mg, 0.92 mmol, 1.1 equiv) are added to a solution of (3S)-3-(tert-butyldimethylsilyloxy)-2-hydroxy-2-methyl-tetrahydrofurane 13 (194 mg, 0.83 mmol) in dimethyl formamide (800 μl). The mixture is stirred for 24 h at r.t. Purification of the reaction mixture by flash column chromatography (pentane/diethyl ether 20:1) affords (S)-3,5-di-(tert-butyidimethylsilyloxy)pentan-2-one 14 (226 mg, 78%) as a colourless oil. [α]D20=−11.8; [α]54620=−14.1 (c=1.0, CHCl3); 1H-NMR (200 MHz, CDCl3): δ(ppm)=4.16 (dd, 1H); 3.8-3.5 (m, 2H); 2.16 (s, 3H); 1.9-1.7 (m, 2H); 0.92 (s, 9H); 0.88 (s, 2H); 0.06 (s, 6H); 0.04 (s, 3H), 0.03 (s, 3H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:9]=[C:8]([CH2:10]OC)[S:7][C:6]=1[CH3:13].B(Cl)(Cl)[Cl:16]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:9]=[C:8]([CH2:10][Cl:16])[S:7][C:6]=1[CH3:13]
Reactant: COCc1cc(CC(=O)OC)c(C)s1
Reactant: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc(CCl)sc1C
Temperature: 0 °C
Yield: 99.6 %

Procedure:
A solution of (5-methoxymethyl-2-methyl-thiophen-3-yl)-acetic acid methyl ester (2.2 g, 10.1 mmol) in dichloromethane (60 mL) is cooled to −65° C. and treated with boron trichloride (10.1 mL, 1.0 M, 10.1 mmol) dropwise via syringe. The mixture is allowed to warm to 0° C., poured into ice-water and extracted with dichloromethane (3×). The combined organic extracts are washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated in vacuo to give (5-chloromethyl-2-methyl-thiophen-3-yl)-acetic acid methyl ester (2.2 g, 99%) as an orange oil. 1H NMR (CDCl 3, 300 MHz) δ 6.90 (s, 1 H), 4.72 (s, 2 H), 3.70 (s, 3 H), 3.50 (s, 2 H), 2.38 (s, 3 H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24](=[O:28])[O:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN1CCCC1=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]=[CH:23][C:24](=[O:28])[O:25][C:26]=2[CH:27]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: NCC1COc2ccccc2O1
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccc(OCCCNCC3COc4ccccc4O3)cc2o1
Temperature: 80 °C
Yield: 29.9 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine (1.7 g, 10 mmole), 7-(3-chloropropoxy)coumarin (2.4 g, 10 mmole), diisopropylethylamine (1.3 g, 10 mmole) and sodium iodide (5.0 g, 33 mmole) were combined in 100 ml of N-methylpyrrolidinone and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with 300 ml of dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 100 g of silica gel using chloroform as eluant. The product-containing fractions (Rf=0.15 on silica gel tlc with 1% methanol/chloroform) were combined and concentrated in vacuum and the residue crystallized from isopropanol with the addition of 4N isopropanolic HCl to give 1.1 g of title compound as a tan solid, monohydrochloride, m.p. 213°-215° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=2)[CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:35]=[C:36]([C:44]([F:46])([F:47])[F:45])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=2)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCN2)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCN2)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To the product from Example 178 (360 mg, 0.0005 mole) in H2O (8 mL) and CH3CN (8 mL) was added LiOH (88 mg, 0.0021 mole). The reaction was stirred at room temperature for 3 hours. The pH was lowered to ~3 with TFA and the product was isolated by RPHPLC to yield the title compound (300 mg after lyophilization) as a white solid.
Reaction SMILES: CON(C)[C:4]([C@@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH3:8])=[O:5].[C:18](=O)=O.CC(C)=O.C[Li].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[C:4](=[O:5])[CH3:18])[CH3:8]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(C)=O
Reaction time: 4 h

Procedure:
A solution of tert-butyl {(1S)-1-[methoxy(methyl)carbamoyl]propyl}carbamate (15.0 g) in tetrahydrofuran (150 mL) was cooled using dry ice/acetone under a nitrogen atmosphere, and 1.0 mol/L-methyllithium/diethyl ether solution (300 mL) was added. The mixture was stirred at the same temperature for 4 hr, saturated aqueous ammonium chloride solution (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentration under reduced pressure to give the title compound as a colorless oil (yield: 12.75 g).