Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:28][S:29][CH3:30]>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:16])[C:3]=1[C:4]([N:6]([CH2:7][CH3:8])[CH2:28][S:29][CH3:30])=[O:5]
Reactant: CSCCl
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CSC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
To a solution of 2.0 g (7.8 mmol) of the compound of Example 45 in 30 mL dry THF was added 7.9 mL (7.9 mmol) sodium bis(trimethylsilyl)amide (1.0 M in THF). To the resulting mixture was added 1.0 g (10.4 mmol) chloromethyl methylsulfide. The mixture was stirred for 15 min and another 0.65 g (6.7 mmol) of chloromethyl methylsulfide was added. Stirring at RT was continued for 1 h and the mixture was then heated to reflux for 28 hours. The mixture was allowed to cool to RT and was then partitioned between ether and water. The organic layer was washed with brine, dried (MgSO4), and was filtered through silica gel. The filtrate was evaporated in vacuo and the residue was chromatographed (HPLC, 8% ethyl acetate/hexane) to yield 1.1 g (45%) of a colorless oil. nD25 =1.5526.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].ClC1C=CC=C(C(OO)=[O:22])C=1>C(OCC)(=O)C>[N+:1]1([O-:22])[C:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 40 h
Yield: 81.4 %

Procedure:
tert-Butyl 2-pyridinecarboxylate (14.0 g, 78 mmol) was dissolved in ethyl acetate (200 ml), and 3-chloroperbenzoic acid (ca. 77%, 26.2 g, 117 mmol) was added thereto. The reaction mixture was stirred at room temperature for 40 hrs. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with ethyl acetate-acetone (1:1, v/v) to give the titled compound (12.4 g, 81%).
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH2:14]2)=[CH:9][CH:8]=1)[CH3:6].C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C.C(O)(=O)C>O1CCCC1.CO>[CH:39]1([N:24]2[CH2:25][CH2:26][N:21]([C:19]([N:17]3[CH2:18][CH:13]([C:10]4[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=4)[CH2:14][CH:15]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[CH2:16]3)=[O:20])[CH2:22][CH2:23]2)[CH2:41][CH2:40]1
Reactant: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N3CCNCC3)C2)cc1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N3CCN(C4CC4)CC3)C2)cc1

Procedure:
At RT, 898 μl of a 1-molar solution of sodium cyanoborohydride in tetrahydrofuran were added to a solution of 94 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenyl-1-(piperazin-1-ylcarbonyl)piperidine-3-carboxamide, 241 μl (1.20 mmol, 6 eq.) of [(1-ethoxycyclopropyl)oxy](trimethyl)silane, 35 μl (0.62 mmol, 3.1 eq.) of acetic acid and 115 mg of molecular sieves (4 {acute over (Å)}) in 1 ml of methanol. The reaction mixture was stirred under reflux for 5 h and then filtered and adjusted to pH 8 using a 0.2-molar sodium hydroxide solution. After addition of water/dichloromethane and phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 60 mg (65% of theory)
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=3[OH:27])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Br[CH2:29][CH:30]([F:32])[F:31].[F-].[Cs+]>CN(C=O)C>[C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:14]=3[O:27][CH2:29][CH:30]([F:32])[F:31])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3O)cccc2s1
Reactant: FC(F)CBr
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC(F)F)cccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the crude 2-acetyl-4-(2-hydroxy-3,5-di-tert-butylphenyl)benzo[b]thiophene, 142.0 mg (1 mmol) of 2-bromo-1,1-difluoroethane and 410 mg (2.7 mmol) of CsF in 10 mL of dry DMF was stirred at room temperature overnight. After work-up the crude oil was filtrated over a short pad of silica gel (eluent: 10/90 ethyl acetate/hexane) to give 2-acetyl-4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thiophene as an oil, directly used without further purification. The crude ketone was treated with the anion of triethylphosphonoacetate (previously prepared from 336 mg of triethylphosphonoacetate and 86 mg of NaH in 3 mL of dry DMF) at 60° C. After completion of the reaction (TLC monitored) and work-up, the crude ester was purified over silica gel column (eluent: 5/95 ethyl acetate/hexane) to afford 315 mg (0.65 mmol, yield: 75%, 2 steps) of pure 3-{4-[2-(2,2-difluoroethoxy)-3,5-di-tert-butylphenyl]-benzo[b]thien-2-yl}-but-2-enoic acid ethyl ester as an oil. 1H-NMR (CDCl3), δ: 7.80 (dd, J=7.2, 1.6 Hz, 1H), 7.43 (m, 4H), 7.23 (d, J=2.5 Hz, 1H), 6.29 (s, 1H), 5.17 (dt, J=55.4, 4.1 Hz, 1H), 4.21 (dd, J=14.4, 7.2 Hz, 2H), 3.50 (m, 2H), 2.57 (s, 3H), 1.47 (s, 9H), 1.34 (s, 9H), 1.31 (t, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:32]2[CH:33]=[CH:34][C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 42 h
Yield: 38.2 %

Procedure:
To a solution of Boc-D-Tyrosine-Methyl ester (0.950 g, 3.217 mmol), 4-Phenoxyphenyl-boronic acid (0.688 g, 3.217 mmol), and triethylamine (228 mL, 16.083 mmol) in anhydrous dichloromethane (DCM) (79.2 mL) at room temperature under an atmosphere of nitrogen was added copper (II) acetate (0.445 g, 3.217 mmol), and the resulting mixture was stirred at room temperature for about 42 hours. The reaction mixture was washed with 60 mL of water and 20 mL of DCM and filtered. The DCM layer was then extracted. The aqueous layer was re-extracted with DCM (2×30 mL). The organic layers were combined, washed with 60 mL of brine, and seperated. Organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.57 g, 50%): 1H NMR (400 MHz, CDCL3): δ 1.42 (s, 9H), 1.59 (s, 1H), 2.99-3.11 (m, 2H), 3.67-3.73 (m, 3H), 4.57 (d, 1H, J=7.2 Hz), 4.99 (d, 1H, J=8 Hz), 6.92 (d, 2H, J=8.8 Hz), 6.99-7.01 (m, 5H), 7.07-7.10 (m, 3H), 7.31-7.35 (m, 2H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O.C(=O)([O-])[OH:20].[Na+]>CC(C)=O.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=[O:20])[CH2:14][CH2:13]2)[N:7]=1
Reactant: O=C([O-])O
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C1CCCCN1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To magnetically stirred ice-water (72 mL) was added a solution of cyanuric chloride (2.2 g, 12 mmol) in acetone (48 mL), followed by piperidone monohydrate hydrochloride (1.8 g, 12 mmol) as a suspension in acetone (20 mL) and water (10 mL). To the mixture was added a suspension of sodium hydrogen carbonate (2.2 g, 24 mmol) in water (25 mL). The mixture was stirred at 0° C. for two hours. The title compound was collected by filtration, washed with water, and dried under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][C@H:9]([CH3:13])[CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:23][CH2:24][C:25]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:8][C@H:9]1[CH3:13])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (3 g, 14.4 mmol) in dichloromethane (40 mL) was added triethylamine (2.0 mL, 14.4 mmol). The reaction was cooled to 0° C. and chloroacetyl chloride was added (1.1 mL, 14.4 mmol). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction is diluted with dichloromethane and washed with 10% citric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (3.9 g).
Reaction SMILES: [OH:1]O.[F:3][C:4]([F:37])([F:36])[C:5]1[CH:27]=[C:26]([S:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:6]=1[NH:7][C:8](=[O:23])[C:9]1[C:10](=[C:12]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16])[OH:11].O>C(O)(=O)C>[F:37][C:4]([F:36])([F:3])[C:5]1[CH:27]=[C:26]([S:28]([C:29]2[CH:30]=[CH:31][C:32]([Br:35])=[CH:33][CH:34]=2)=[O:1])[CH:25]=[CH:24][C:6]=1[NH:7][C:8](=[O:23])[C:9]1[C:10](=[C:12]([C:19]([CH3:21])([CH3:22])[CH3:20])[CH:13]=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16])[OH:11]
Reactant: OO
Reactant: Cc1c(C#N)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(Sc2ccc(Br)cc2)cc1C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(C#N)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(S(=O)c2ccc(Br)cc2)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
30% w/v Aqueous hydrogen peroxide solution (70 μl.) is added to a suspension of 2'-trifluoromethyl-4'-(4-bromophenylthio)-5-cyano-3-t-butyl-6-methylsalicylanilide (0.25 g.) in acetic acid (4 ml.), and the mixture heated at 70°-80° C. for 1 hour. Water (2 ml.) is then added and the solution is cooled slowly to room temperature. The crystalline solid which is thus obtained is separated by filtration and dried to give 2'-trifluoromethyl-4'-(4-bromophenylsulphinyl)-5-cyano-3-t-butyl-6-methylsalicylanilide, m.p. 178°-180° C.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:20]2[CH2:32][C:23]3[NH:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][C:30]=4[C:22]=3[CH2:21]2)([F:19])[C:11]2[O:15][N:14]=[C:13]([C:16]([NH2:18])=O)[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]1([S:7]([C:10]([CH:20]2[CH2:32][C:23]3[NH:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][C:30]=4[C:22]=3[CH2:21]2)([F:19])[C:11]2[O:15][N:14]=[C:13]([C:16]#[N:18])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
To a stirred solution of 170 mg (0.35 mmol) of (RS,SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carboxylic acid amide in 2 mL acetonitrile at RT was added 0.5 mL phosphorous oxychloride. The dark brown solution was stirred for 1 hour and then the temperature was raised to 50° C. and stirred overnight. After cooling down to RT, 0.5 mL phosphorous oxychloride were added. The reaction mixture was stirred for 2 hours under reflux condition. The solvent was partially evaporated and the resulting oil was dissolved with EtOAc and washed with saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (EtOAc/heptane 1:1) yielded 20 mg (12%) (RS, SR)-5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazole-3-carbonitrile as a light red solid, MS: 457 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][N:5]2[C:14]3C(=[CH:10][CH:11]=[CH:12][CH:13]=3)NC(=O)[C:6]=12.IC.[C:22](=O)([O-])[O-].[Cs+].[Cs+].[CH3:28][N:29]([CH:31]=[O:32])[CH3:30]>>[CH3:22][O:1][C:2]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][N:5]2[C:14]3[C:28](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:29]([CH3:30])[C:31](=[O:32])[C:6]=12
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nn2c(c1O)c(=O)[nH]c1ccccc12
Agent: [Cs+]
Solvent: CI
Product: COC(=O)c1nn2c(c1OC)c(=O)n(C)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-hydroxy-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-2-carboxylate (525 mg, 2.02 mmol) in DMF (5 mL) under inert atmosphere was added iodomethane (1.0 g, 7.0 mmol) and cesium carbonate (1.6 g, 5.0 mmol). The mixture was stirred at ambient temperature for 18 hours. The solvent was removed under reduced pressure and the residue was suspended in EtOAc. The solids were removed by filtration. The filtrate solvent was removed under reduced pressure to give the product as an oil. ES MS (M+1)=288.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:4]=1[CH:5]=O.[OH2:18].Cl.[NH2:20]O.C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:4]=1[CH:5]=[N:20][OH:18]
Reactant: O
Reactant: COc1ccc(Oc2ccccc2)cc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2ccccc2)cc1C=NO
Yield: 98 %

Procedure:
2-Methoxy-5-phenoxybenzaldehyde (4.5 g, 19.7 mmol) was dissolved in 60 ml of warm methanol. Water (40 ml) was added to this solution followed by the addition of hydroxylamine hydrochloride (2.7 g, 38.9 mmol) and anhydrous sodium acetate (6.5 g, 79.2 mmol). This mixture was then refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the methanol. The residue was partitioned with ethyl acetate. The ethyl acetate layer was separated, washed five times with water, dried (anhydrous MgSO4) and the solvent removed under reduced pressure to give 2-methoxy-5-phenoxybenzaldehyde oxime as a white crystalline solid (4.70 g, 98%), mp 95°-100° C.
Reaction SMILES: Br.[CH3:2][C:3]1[N:4]=[C:5]([NH2:20])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:9]=1.C(N(C(C)C)C(C)C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[CH3:2][C:3]1[N:4]=[C:5]([NH:20][C:30](=[O:32])[CH3:31])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:9]=1
Reactant: Cc1nc(N)sc1-c1ccnc(N2CCOCC2)c1
Reactant: CC(=O)OC(C)=O
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)c2)s1
Temperature: 75 °C

Procedure:
A stirred suspension of 4-methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-ylamine hydrobromide (13b) (0.035 g, 0.098 mmol) and ethyldiisopropylamine (0.034 ml, 0.196 mmol) in acetic anhydride (2 ml) is heated to 75° C. for 2 hours. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. Ethyl acetate is added and a white solid by-product is filtered off. The filtrate is concentrated in vacuo to afford the titled compound as a white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][OH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>C1COCC1>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:12][CH2:11][CH2:10][C@@H:9]([C:13]([OH:15])=[O:14])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccc(Br)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a flask containing Boc-L-homoserine (5.181 g, 23.63 mmol)) in THF (50 ml) was added sodium hydride (2.93 g, 73.3 mmol) and left stirring at 0° C. for 30 minutes. The reaction mixture was warmed to RT and left for 2 hrs. 4-bromo-benzylbromide (11.81 g, 47.3 mmol) was then added as a THF solution (15 ml) dropwise. The reaction was left at RT for 20 hrs. The reaction was quenched with MeOH and the solvent removed in vacuo. The residue was dissolved in water and washed with Et2O. The aqueous layer was acidified with 2M HCl and exhaustively extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo. The oily residue (11 g) was purified by column chromatography eluting with 50-100% EtOAc in hexanes and flushed with 10-50% MeOH in EtOAc. Yield=927 mg, 2.388 mmol, 10% yield as a viscous oil. m/z 386/388 [M−H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21].[H][H].Cl[C:34]([O:36][CH3:37])=[O:35]>C1COCC1>[F:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:18][CH3:19])[C:10]=2[C:14]([F:17])([F:16])[F:15])[C:5]=1[C:20]([N:22]([C:34]([O:36][CH3:37])=[O:35])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21]
Reactant: COC(=O)Cl
Reactant: COc1ccc2c(C(=O)NCC(=O)OC(C)(C)C)c(F)ccc2c1C(F)(F)F
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Sodium hydride (80% dispersion in mineral oil, 1.81 g, 1.1 eq) was added to a stirred, room temperature solution of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine, 1,1-dimethylethyl ester (21.98 g, 54.76 mmol) in dry THF (450 mL) under a dry N2 atmosphere. The suspension was heated in a 50° C. oil bath until hydrogen evolution ceased (approximately 2 hours). The reaction mixture was cooled to 0°-5° C. and a solution of methyl chloroformate (5.76 mL, 1.36 eq) in dry THF (150 mL) was added dropwise over a 20 minute period. The reaction mixture was then warmed to room temperature and stirred for 30 minutes. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with ether (500 mL). Silica gel (100 mL) was added and the solvents were removed in vacuo. The silica absorbate was flash chromatographed (gradient elution 4:1 to 7:3 petroleum ether:ethyl acetate, silica) to provide the title compound as a white solid (18.79 g, 75%) and starting material (3.07 g, 14%). A small portion was recrystallized from petroleum ether:ether for analysis; m.p. 111°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]([C:29]2([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][N:19]=3)[S:17][C:10]=12.[CH3:41][O:42][CH2:43][CH2:44][NH2:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:26]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]([C:29]2([C:32]([NH2:34])=[O:33])[CH2:31][CH2:30]2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:20][N:19]=3)[S:17][C:10]=12
Reactant: COCCN
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(-c5ccc(C=O)cn5)sc34)c(F)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccccc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Aldehyde 141 (0.20 g, 0.362 mmol) and 2-methoxyethylamine (0.158 mL, 1.810 mmol) were dissolved in THF (50 mL) to give a colorless solution. Sodium trisacetoxyborohydride (0.384 g, 1.810 mmol) was added and the mixture was stirred at r.t. for 20 h. Additional 2-methoxyethylamine (0.158 mL, 1.810 mmol) and sodium trisacetoxyborohydride (0.384 g, 1.810 mmol) were added, and the mixture was stirred for a further 20 h. It was then concentrated, partitioned between water and dichloromethane. Organic phase was collected, washed with H2O, 1M NaOH, and brine, dried (MgSO4), filtered and concentrated. The residue was purified by Gilson Reverse Phase HPLC (Aquasil C18, 40-90% MeOH/water, 30 min, elutes 20 min) and lyophilized, to afford title compound 142. Starting material (50 mg) was also isolated.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29].CC([O:37]C([C@H](O)[C@@H](O)C(OC(C)C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]([CH:17]1[CH:16]([C:15]([CH3:19])([CH3:18])[CH3:14])[O:37]1)[OH:29]
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Reactant: O=Cc1ccccc1Br
Reactant: C#CC(C)(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C1OC1C(O)c1ccccc1Br
Yield: 78 %

Procedure:
The product was prepared by General procedure T using 50 mg (0.28 mmol) Cy2BH, 35 μL (0.28 mmol) 3,3-dimethyl-1-butyne, 0.39 mL (0.78 mmol, 2.0 M in hexanes) Et2Zn, 2.4 mg (0.01 mmol) (−)-MIB, 29 μL (0.25 mmol) o-bromobenzaldehyde, 0.25 mL (0.25 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 63 μL (0.30 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 78% yield (55 mg, 0.19 mmol). threo-diastereomer: Colorless oil. [α]D20=−65.8 (c=0.40, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.90 (s, 9H), 2.55 (d, 1H, J=5.2 Hz), 3.08 (m, 2H), 5.00 (t, 1H, J=4.6 Hz), 7.18 (t, 1H, J=7.6 Hz), 7.37 (t, 1H, J=7.5 Hz), 7.55 (d, 1H, J=7.9 Hz), and 7.61 (d, 1H, J=7.3 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 25.7, 30.6, 58.2, 65.2, 71.7, 122.0, 127.88, 127.94, 129.4, 132.8, and 140.0 ppm; IR (neat): 3418, 3060, 2957, 2872, 2343, 1568, 1469, 1437, 1396, 1365, and 1190 cm−1; HRMS-CI m/z 267.0368 [(M−OH)+; calcd for C13H16BrO: 267.0385]. erythro-diastereomer: Colorless oil. [α]D20=−55.5 (c=0.53, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.84 (s, 9H), 2.42 (br d, 1H, J=2.1 Hz), 2.85 (br d, 1H, J=2.3 Hz), 3.29 (t, 1H, J=2.4 Hz), 5.40 (br s, 1H), 7.17 (t, 1H, J=7.4 Hz), 7.34 (t, 1H, J=7.4 Hz), 7.51 (d, 1H, J=7.7 Hz), and 7.54 (d, 1H, J=8.0 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 25.7, 30.3, 56.5, 62.3, 69.1, 122.1, 127.7, 127.9, 129.4, 132.6, and 138.9 ppm; IR (neat): 3426, 3060, 2958, 2861, 1631, 1590, 1586, 1467, 1439, 1390, and 1364 cm−1; HRMS-CI m/z 267.0368 [(M−. OH)+; calcd for C13H16BrO: 267.0385].