Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.Cl.[NH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)CCC>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][CH:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH:16][CH:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:7]=1
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Reactant: NC1CCC(O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: OC1CCC(Nc2cc(-c3ccccc3)nc(Cl)n2)CC1
Product: OC1CCC(Nc2nc(Cl)cc(-c3ccccc3)n2)CC1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of compound 2,4-dichloro-6-phenyl-pyrimidine (0.5 g, 2.22 mmol), 4-aminocyclohexanol hydrochloride (0.12 g, 1.11 mmol), triethylamine (0.67 g, 6.62 mmol) in n-butanol (10 mL) was stirred at 120° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was then concentrated under vacuum, diluted with water (25 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were collected, combined, washed with water (20 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The residue thus obtained was purified by column chromatography using ethyl acetate-petroleum ether to give the two compounds 4-(2-chloro-6-phenyl-pyrimidin-4-ylamino)-cyclohexanol and 4-(4-chloro-6-phenyl-pyrimidin-2-ylamino)-cyclohexanol in ratio 1:2 (overall yield: 63%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:20]([CH2:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=O)=[O:4].Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>C(O)C>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[C:7]2[CH:17]=[CH:18][CH:19]=[C:20]([CH2:21][CH3:22])[C:6]=2[NH:5][C:3](=[O:4])[CH2:2][N+:24]=1[O-:25]
Reactant: NO
Reactant: CCc1cccc(C(=O)c2ccccc2F)c1NC(=O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc2c1NC(=O)C[N+]([O-])=C2c1ccccc1F
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 94.1 %

Procedure:
A mixture of 2-bromoacetylamino-3-ethyl-2′-fluorobenzophenone (12.0 g), hydroxylamine hydrochloride (17.65 g), sodium hydroxide (8.58 g) in ethanol was stirred at 30-40° C. for 4.5 hours. Concentrated aqueous hydrochloric acid (14.8 ml) was added to the reaction mixture, which was stirred at room temperature overnight. The mixture was evaporated in vacuo to afford precipitates. Water was added to the resultant mixture. The precipitate was collected by filtration and washed with water to afford 5-(2-fluorophenyl)-9-ethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (9.25 g, 94.2%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:21]=3)[CH2:16][CH:15]2[C:34](O)=[O:35])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl.[CH3:47][NH:48][CH:49]=[CH:50][CH2:51][CH2:52][CH2:53][CH3:54].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:21]=3)[CH2:16][CH:15]2[C:34](=[O:35])[N:48]([CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[CH3:47])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: CCCCC=CNC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(OC)nc(-c3ccccc3)n2)CC1C(=O)O)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(OC)nc(-c3ccccc3)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C

Procedure:
Compound 7b (1.32 g, 2.67 mmol) was dissolved in 30 ml dry DMF. DIEA (2.1 ml, 12.0 mmol), N-methylhexeneamine HCl (440 mg, 3.9 mmol) and HATU (1.48 g, 3.9 mmol) were added at 0° C., and the reaction mixture was stirred at RT over night. The DMF was evaporated and the residue was dissolved in EtOAc, washed with sat. NaHCO3(aq), H2O and brine. The organic layer was dried (MgSO4), filtered and evaporated, followed by column chromatography (Heptane/EtOAc), giving the title compound. (1.1 g, 70%), MS (M+H)+591.
Reaction SMILES: [AlH4-].[Li+].[CH:3]1[C:8]([C@H:9]([NH2:13])[C:10](O)=[O:11])=[CH:7][CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[CH:4]=1>O1CCCC1>[NH2:13][C@@H:9]([C:8]1[CH:3]=[CH:4][C:5]([C:14]([F:15])([F:16])[F:17])=[CH:6][CH:7]=1)[CH2:10][OH:11]
Reactant: N[C@H](C(=O)O)c1ccc(C(F)(F)F)cc1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@H](CO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
Lithium tetrahydroaluminate (0.62 g, 0.016 mol) was added slowly, in small portions, to an ice cooled mixture of 4-(trifluoromethyl)-L-phenylglycine (1.8 g, 8.2 mmol) in tetrahydrofuran (60 mL). The mixture was slowly warmed to rt over a period of 1 h and then heated to reflux overnight. The solution was cooled to 0° C. and quenched with 2.0 M aqueous NaOH solution. The precipitate was filtered off and the filter cake was washed with THF. The filtrate was concentrated and extracted with CH2Cl2 (50 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo to give a light yellow solid (0.9 g, 59%). LC-MS: 206.2 [M+1]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].ClC(Cl)(Cl)C(=N)O[C:59]([CH2:61][CH3:62])=[CH2:60].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:59]([CH2:61][CH3:62])=[CH2:60])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: C=C(CC)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=C(CC)OC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg in 3 ml 33% methylene chloride in cyclohexane), sec-butenyl trichloroacetimidate (62 μl neat) is added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) is then added slowly via syringe and the mixture stirred at room temperature. After 15 minutes the reaction is quenched by the addition of saturated sodiumbicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics are washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel the title compounds.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)=[N:10]1.Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[N:26]=[CH:25][N:24]([CH3:27])[N:23]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Yield: 45.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1-methyl-1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 1 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.17 g, 1 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.25 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH3:13][C:14]([CH3:20])([CH2:17][CH:18]=[CH2:19])[CH2:15][OH:16].Cl.[NH2:22][C@@H:23]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:24]([O:26][CH3:27])=[O:25]>CN(C=O)C>[CH:28]1([C@H:23]([NH:22][C:6]([O:16][CH2:15][C:14]([CH3:20])([CH3:13])[CH2:17][CH:18]=[CH2:19])=[O:7])[C:24]([O:26][CH3:27])=[O:25])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC(=O)[C@@H](N)C1CCCCC1
Reactant: C=CCC(C)(C)CO
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)OC)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
CDI (1.42 g, 8.76 mmol) was added to a solution of 2,2-dimethylpent-4-en-1-ol [Ref.: E. Alexander Hill et al., 46(6) J. Org. Chem. 1177-82 (1981).] (1.00 g, 8.76 mmol) in DMF (12 mL) cooled with a water bath. The mixture was stirred for 30 minutes at RT. Methyl (2S)-amino(cyclohexyl)acetate hydrochloride (1.82 g, 8.76 mmol) was then added, and the mixture was heated to 50° C. for 16 hours and then cooled to RT. The reaction mixture was partitioned between EtOAc and water/1N HCl. The organic layer was extracted with water (3×) and brine. The organic layer was then dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel (gradient elution, 0-10% EtOAc/hexane) to yield the title product (2.04 g, 75% yield). LRMS ESI+ (M+H)+ 312.5.
Reaction SMILES: [Cl-].[Na+].[OH:3][C:4]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:6][C:5]=1C(OC)=O>CS(C)=O.O>[C:15]1([CH:7]2[O:6][CH2:5][C:4](=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C1=C(O)c2ncccc2CC(c2ccccc2)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1COC(c2ccccc2)Cc2cccnc21
Temperature: 150 °C

Procedure:
Sodium chloride (0.10 g, 1.7 mmol) was added to a solution of methyl 9-hydroxy-6-phenyl-5,6-dihydrooxepino[4,5-b]pyridine-8-carboxylate (0.50 g, 1.7 mmol) in dimethylsulfoxide (8 mL) and water (0.4 mL). The resulting mixture was heated at 150° C. for 2 h, then cooled and partitioned between water and ethyl acetate (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in petroleum ether to give the title compound. MS: m/z=240.0 (M+1).
Reaction SMILES: Cl.Cl.Cl.[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[CH3:21].C(N(CC)C(C)C)(C)C.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1>C(Cl)Cl>[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[N:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=2)=[O:39])=[CH:16][C:15]=1[CH3:21]
Reactant: Cc1cc(N)ccc1N1CCc2ccncc2C1
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)c(C)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-3-methylaniline trihydrochloride (24.7 mg, 0.071 mmol) and N,N-diisopropylethylamine (0.043 mL, 0.25 mmol) in 1.0 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.013 mL, 0.106 mmol) and the reaction stirred at rt for 1.5 hours. The reaction was quenched into a brine/aqueous Na2CO3 solution, then extracted with EtOAc. The EtOAc layer was washed with brine/aqueous Na2CO3 solution, dried with anhydrous Na2SO4, and evaporated to an oily solid. The oil was chromatographed eluting with CHCl3/EtOAc plus 0.5% MeOH to give the title compound as a faint yellow solid (26 mg, 97%). 1H NMR (Acetone-d6) δ: 8.35 (s, 1H), 8.32 (d, J=5.0 Hz, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.29-7.40 (m, 4H), 7.08-7.17 (m, 3H), 6.80 (d, J=7.3 Hz, 1H), 4.07 (s, 2H), 3.15-3.20 (m, 2H), 2.97-3.03 (m, 2H), 2.30 (s, 3H), 2.29 (s, 3H)
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8](/[CH:9]=[N:10]/[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[Li+].C(N(CC)CC)C.[CH:28]([S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])=[CH2:29].C(OC(C)=O)(C)C>C1COCC1>[CH2:15]([O:14][C:12]([CH:11]1[CH2:29][CH:28]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:31])=[O:32])[CH:9]([C:8]2[CH:17]=[CH:18][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[NH:10]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C/N=C/c1ccc(C(C)(C)C)cc1
Reactant: C=CS(=O)(=O)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccc(C(C)(C)C)cc2)N1
Temperature: 0 °C
Yield: 8 %

Procedure:
To a stirred solution of (E)-ethyl 2-(4-tert-butylbenzylideneamino)acetate (226 mg, 914 umol; example 441a) in THF (5 ml) under an argon atmosphere were added lithium bromide (119 mg, 1.37 mmol), triethylamine (191 ul, 1.37 mmol) and phenyl vinyl sulfone (154 mg, 914 umol; CAS Reg. No. 5535-48-8). The mixture was stirred at ambient temperature for 20 h. iPrOAc (50 ml) and ice water (40 ml) were added and the layers were separated. The organic layer was washed with brine (40 ml), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, iPrOAc/n-heptane) to obtain the title compound (56 mg, 73 umol; 8%) as colorless solid. MS (ESI): m/z=416.2 [M+H]
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[F-:13].[K+].[F-].[Ca+2].[F-]>C(#N)C>[F:13][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: [F-]
Agent: [Ca+2]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CF)cc1
Yield: 78.7 %

Procedure:
Dry acetonitrile (150 ml) was added to 25.00 g of methyl 4-(bromomethyl)benzoate, 19.02 g of potassium fluoride and 9.51 g of calcium fluoride, and the mixture was heated to reflux for 3 days. The reaction solution was concentrated. After addition of 200 ml of acetonitrile, insolubles were removed by filtration, and the filtrate was concentrated again. The residue was purified by silica gel column chromatography (YMC•GEL® SIL-60-230/70, n-hexane:ethyl acetate=10:1–4:1), followed by distillation under reduced pressure to provide 14.45 g of the objective compound as colorless oil. B.p. 118.5–119° C./18 mmHg.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5]([C:8]1[Se:9][C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:12](=O)[CH:13]=1)([CH3:7])[CH3:6].[F:19][B-:20]([F:23])([F:22])[F:21].[H+]>O1CCCC1>[F:19][B-:20]([F:23])([F:22])[F:21].[CH3:4][C:5]([C:8]1[CH:13]=[C:12]([CH3:1])[CH:11]=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[Se+:9]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1cc(=O)cc(C(C)(C)C)[se]1
Reactant: C[Mg]Cl
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)[se+]c(C(C)(C)C)c1
Temperature: -20 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Methyl magnesium chloride (40 mL of a 3 M solution in tetrahydrofuran, 0.12 mol) was added to a solution of 2,6-bis[1,1-dimethylethyl]selenopyran-4-one (22 g, 0.081 mol, prepared in Part C above ) in dry tetrahydrofuran (100 mL) which was initially maintained at -20° C. using a cold bath; the addition was effected at such a rate that the temperature in the reaction vessel did not exceed -15° C. The cold bath was removed, and the pale yellow solution was allowed to stir at room temperature for four hours, during which time a thick slurry formed. The mixture was then poured into ice/water (1 L) with rapid agitation, and tetrafluoroboric acid (200 mL of a 48% aqueous solution) was added. Stirring was continued for a further two hours, after which the mixture was extracted with dichloromethane (3×100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a tan residue, which was triturated with ether. The solid which resulted was collected by filtration, washed with ether and dried to give 2,6-bis(1,1-dimethylethyl)-4-methylselenopyrylium tetrafluoroborate (24.7 g, 85% yield) as an off-white solid which melted at 65°-66° C. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[C:19]([Cl:26])[CH:18]=1>CCCCC.ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:14][C@H:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:25])=[C:19]([Cl:26])[CH:18]=1
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Reactant: O=C=Nc1ccc(Br)cc1Cl
Solvent: CCCCC
Solvent: ClCCl
Product: CC1(C)OC[C@H](NC(=O)Nc2ccc(Br)cc2Cl)[C@H](c2ccccc2)O1
Yield: 87.2 %

Procedure:
To a stirred or shaken solution of 157 mg (0.76 mmol) of (4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-amine (abbreviated as (4S,5S)-amine 1) in pentane (3.5 mL) was added dropwise a solution of 169 mg (0.73 mmol) of 4-bromo-2-chlorophenyl isocyanate in dichloromethane (0.7 mL). A white precipitate was observed after stirring for 0.5 to 2 h. The precipitate was collected, rinsed with pentane, and dried under vacuum to yield 280 mg (88%) of the title compound. In some examples, pentane was used to dissolve the required isocyanate rather than dichloromethane. In addition, if the required isocyanate was a liquid, it was added dropwise as a neat liquid on small-scale reactions such as this. In cases where a precipitate was not observed or the precipitate was not of sufficient purity, the solvent was evaporated, and the residue was purified by column chromatography (hexanes/ethyl acetate) to yield the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCCCCCCCl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 89.2 %

Procedure:
A mixture of 16.7 g (100 mmol) of 5-hydroxy-2-nitrobenzaldehyde, 32 g (110 mmol) of 6-chlorohexyl-p-toluenesulfonate and 17 g of potassium carbonate in dry 250 ml of DMF was heated to 100° C. under dry nitrogen for 3 h. The reaction was cooled, filtered and evaporated to a dark oil. The crude product was dissolved in 500 ml of ethyl acetate, and the organic layer was washed twice with 300 ml of saturated sodium carbonate, and twice with 300 ml of brine, dried, filtered and evaporated. Filtration through silica gel gave 25.5 g (89.2 mmol, 89%) of 5-(6-chlorohexyl)oxy-2-nitrobenzaldehyde as a green syrup unstable to distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10][CH:11]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=1.C1(C2OC(C(F)(F)F)=C(COC(=O)C3C=CC(CC(SCCC4C=CC(F)=CC=4)C(OCC(Cl)(Cl)Cl)=O)=CC=3)N=2)C=CC=CC=1>>[CH3:42][S:39]([O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][C:13]([CH2:12][CH:11]([S:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:27])[Cl:28])=[O:23])=[CH:14][CH:15]=2)=[CH:33][CH:34]=1)(=[O:41])=[O:40]
Reactant: O=C(O)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CS(=O)(=O)Oc1ccc(CO)cc1
Agent: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Product: CS(=O)(=O)Oc1ccc(COC(=O)c2ccc(CC(SCCc3ccc(F)cc3)C(=O)OCC(Cl)(Cl)Cl)cc2)cc1
Yield: 53.1 %

Procedure:
The title compound was prepared from 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxycarbonyl)-ethyl]-benzoic acid (65 mg, 0.135 mmol) and methane-sulfonic acid 4-hydroxymethyl-phenyl ester (27.4 mg, 0.136 mmol) in the same manner as described for 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid 2-phenyl-5-trifluoromethyl-oxazol-4-ylmethylester. The crude product was purified by flash chromatography using n-heptane/EtOAc 7:3 as the eluent to afford the final product as an oil (47.6 mg, 45%). 1H NMR (400 MHz, CDCl3): δ 7.95-7.97 (d, 2H), 7.47-7.49 (d, 2H), 7.24-7.29 (m, 4H), 7.07-7.08 (m, 2H), 6.91-6.95 (m, 2H), 5.33 (s, 2H), 4.62-4.75 (dd, 2H), 3.55 (t, 1H), 3.25 (t, 1H), 3.13 (s, 3H), 2.79-3.04 (m, 6H). Mass Spectrum: M−H+ 663.04.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8]COC)[CH:5]=[CH:4][C:3]=1[C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>CC#N.O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: COCOc1ccc(C(=O)CCc2ccc(OC)nc2)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1ccc(CCC(=O)c2ccc(O)cc2O)cn1
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To a solution of 1-(2-hydroxy-4-(methoxymethoxy)phenyl)-3-(6-methoxypyridin-3-yl)propan-1-one (1.62 g, 5.11 mmol) in CH3CN (30 ml) at room temperature was added TFA (2 ml) dropwise, two drops of water. The reaction was stirred at same temperature for 8 h. Aqueous 1N NaOH was added to the reaction mixture until pH=7. The aqueous was extracted with 100 ml EtOAc, and the organic layers were combined. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (15% EtOAc/Hexane) to provide 0.5 g (35%) of white solid.