Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][OH:15]>C(O)C.C(O)(=O)C.ClCCl>[C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[N:14][OH:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: ON=C1CCC(c2ccccc2)CC1

Procedure:
To a stirred solution of 4-phenylcyclohexanone (5 g) in ethanol (100 ml) and acetic acid (16.4 ml) was added aqueous hydroxylamine (50%, 4.5 ml). The reaction was heated at reflux for 16 h, before being allowed to cool, and diluted with dichloromethane (100 ml). The reaction was washed with aqueous sodium bicarbonate (sat, 2×50 ml), the organic layer dried over magnesium sulphate (2 g) and the solvent removed in vacuo to yield a white solid. This was purified by flash chromatography (silica, eluent 50% ethyl acetate/hexane), to yield the title compound as a white solid (5.1 g).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6](#[N:9])[CH:7]=[CH2:8]>>[C:6]([C@H:7]1[CH2:1][CH2:2][C:3]([CH3:5])=[CH:4][CH2:8]1)#[N:9]
Reactant: C=CC#N
Reactant: C=CC(=C)C
Product: CC1=CC[C@@H](C#N)CC1

Procedure:
363 g of 4(5)-cyano-1-methyl cyclohexene (isomer mixture obtained by the cyclo addition of isoprene and acrylonitrile) were incrementally added to a mixture of 5.4 moles of 88% sulphuric acid and 891 g of hydrocyanic acid at 27° C. to 29° C. over a period of 75 minutes, with stirring, wherein the heat of reaction was removed by refluxing the boiling hydrocyanic acid. Ten minutes after completion of the addition, 900 g of water were added and the excess hydrocyanic acid was distilled off. 735 g of a 25% aqueous ammonia solution were then added at 20° C. to 30° C. The neutralized reaction solution obtained was then extracted five times, in each case with 150 g of isobutanol. After removing the extracting agent, 525 g of crude 1-formamido-1-methyl-3(4)-cyano cyclohexane (isomer mixture) (88.5% yield, determined by gas chromatography) was obtained. The isobutanol dissolved in the aqueous ammonium sulphate solution obtained following extraction was removed by distillation. The aqueous ammonium sulphate solution (1800 g, sulphur content: 9.5%, corresponding to 39.5% ammonium sulphate), which remained and from which isobutanol had been removed, had a chemical oxygen demand (COD) of 3500 mg/l.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+].[Ru](=O)=O>[C:7]([OH:2])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccccc1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a stirred suspension of 20 g (94 m mol) sodium periodate in 200 cc of 1 molar sodium hydroxide there was added 0.1 g (0.75 m mol) ruthenium dioxide and 4.32 g (40 m mol) benzyl alcohol. After two hours the reaction was stopped. The mixture was then filtered and the filtrate washed with ether obtaining a neutral fraction comprising benzaldehyde and unreacted benzyl alcohol. The aqueous alkali phase was acidified with sulfuric acid and extracted with ether. There was obtained 4.32 grams of benzoic acid (89% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:18])[NH:7]2.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:1][C:2]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:18])[NH:7]2
Reactant: Sc1ccccc1
Reactant: O=c1ccc2c(Br)c(OCCCCBr)ccc2[nH]1
Product: O=c1ccc2c(Br)c(OCCCCSc3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 5-bromo-6-(4-bromo-butoxy)-carbostyril [prepared by bromination of 6-(4-bromo-butoxy)-carbostyril] and thiophenol.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[CH2:6][N:7]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]1[C:13]([O:15][CH3:16])=[O:14])([O-])=O>O1CCCC1.C(OCC)C.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:1][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[CH2:6][N:7]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Cl)n1Cc1ccccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(Cl)n1Cc1ccccc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2.68 g of methyl 1-(2-nitrobenzyl)-5-chloropyrrole-2-carboxylate in 30 mL of anhydrous tetrahydrofuran is added 35 mL of titanium trichloride in a dropwise manner over a 15 minute period. The reaction is allowed to stir at room temperature for 18 hours and then is diluted with 150 mL of a 1:1 mixture of diethyl ether and water. The organic phase is separated, washed with brine and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and evaporated to dryness to yield methyl 1-(2-aminobenzyl)-5-chloropyrrole-2-carboxylate which is used in the next step without further purification.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[S:44][C:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[S:44][C:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:42][CH:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2cnc(-c3ccccc3)s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cnc(-c3ccccc3)s2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.83 g), sodium hydrogen carbonate (2.94 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-6-oxo-1-[(2-phenyl-1,3-thiazol-5-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.93 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.6 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[N:12][C:11]=1[C:19]([OH:21])=O.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[OH:28][C@@H:26]([CH3:27])[CH2:25][O:24][NH:23][C:19]([C:11]1[N:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: C[C@H](O)CON
Reactant: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O)CONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.8 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid (85 mg, 0.21 mmol) in anhydrous DMF (1.0 mL) was added (S)-1-aminooxy-propan-2-ol hydrochloride (32.7 mg, 0.26 mmol, 1.2 eq.), DIPEA (0.13 mL, 0.77 mmol, 3.6 eq.), HOBt (36.0 mg, 0.26 mmol, 1.2 eq.) and EDCI (51.2 mg, 0.26 mmol, 1.2 eq.), and the reaction mixture was stirred at ambient temperature under N2 for 16 hours. The reaction mixture was poured into ethyl acetate, and the organic layer was washed with a saturated solution of sodium bicarbonate, 50% brine and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 40%, methanol in ethyl acetate) to give an oil. Crystallization from dichloromethane—ether—hexane afforded the title compound as a yellow solid (10.7 mg, 10.6%). 1H NMR (MeOD, 400 MHz) δ ppm 8.76 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.64 (dd, J=10.13, 1.84 Hz, 1H), 7.55-7.50 (m, 1H), 6.72 (t, J=8.49 Hz, 1H); LCMS (method E1): RT=5.14 min, [M+H]+=472.
Reaction SMILES: [CH:1]([N:4]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:18]C)[O:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])([CH3:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH2:17][C@@H:8]([N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6][CH3:7])[CH2:9][O:10]2
Reactant: CCCN(C(C)C)[C@H]1COc2cccc(OC)c2C1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(C(C)C)[C@H]1COc2cccc(O)c2C1
Temperature: -60 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
The HCl-salt of (R)-3-(N-isopropyl-N-n-propylamino)-5-methoxychroman (15.5 g, 52 mmol) was mixed with CH2Cl2 (100 mL) under nitrogen atmosphere and cooled to -60° C. BBr3 (27.2 g, 110 mmol) dissolved in CH2Cl2 (50 mL), was added slowly. The temperature was then raised to 0° C. and the reaction mixture was stirred at 0° C. for 12 h. The reaction mixture was then slowly added to a stirred saturated NaHCO3 solution. The layers were separated and the water layer was extracted once with CH2Cl2. The combined organic layers were dried (MgSO4). Removal of the solvent in vacuo gave the phenolic title compound. Yield: 98%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[C:11](=[O:12])[CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[O:6]1.[BH4-].[Na+].O>CO>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[CH:11]([OH:12])[CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[O:6]1
Reactant: COC(=O)C1(CCCCl)Oc2ccccc2CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1(CCCCl)Oc2ccccc2CCC1O

Procedure:
To a suspension of 2.0 g of methyl 2-(3-chloropropyl)-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate obtained in Reference Example 1 in 30 ml of methanol, sodium borohydride is added in small portions with stirring and under ice-cooling. After completion of the reaction, the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=3:1→1:1). From the first fraction eluted, methyl 2-(3-chloropropyl)-3-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate (A isomer) is obtained as a colorless oil. Mass spectrum m/e: 298, 300 (M+). IR νmaxneat cm-1 : 3500 (OH), 1735. NMR(CDCl3) δ: 2.0 (6H, multiplet), 3.0(2H, multiplet), 3.5 (2H, triplet, ClCH2 --), 3.70 (3H, s, OCH3), 4.18 (1H, multiplet, C3 --H).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1B(O)O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Yield: 79 %

Procedure:
Ex-36A: 2-(5-Formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid in a similar manner as described in Ex-3A. Yellow oil, 79% yield. 1H-NMR (CDCl3) δ 10.36 (s, 1H), 8.15 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.45 (d, J=8 Hz, 3H), 7.27–7.35 (m, 1H), 7.19–7.27 (m, 1H), 6.52 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[CH:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-:34])=[CH:17][C:16]=2[N:15]=[CH:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCn1cnc2c[n+]([O-])c3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
19.47 g (57.19 mmol) of 1-[4-(tert-Butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]quinoline was dissolved in 500 ml of methylene chloride and 15.51 g (62.91 mmol) of 70% m-chloroperbenzoic acid was added thereto. The resulting mixture was stirred overnight at room temperature. A sodium hydrogencarbonate aqueous solution was added to the reaction mixture and the reaction mixture was extracted twice with chloroform. The organic phase was washed with brine and dried (Na2SO4). The solvent was distilled off under reduced pressure and the residue was purified by aluminum column chromatography (chloroform:methanol=50:1 to 10:1 (v/v)). Finally, the resulting product was triturated with diethyl ether and collected by filtration to obtain 15.88 g (44.55 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]quinoline-5-oxide shown below as yellowish white powder. ##STR54## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3280, 2970, 1710, 1540, 1365, 1250, 1170, 1140, 850, 760, 630.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1.CC(CC(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:12][C:9]1[CH:8]=[N:7][C:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([O:1][C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=3)[CH:3]=2)=[N:11][CH:10]=1
Reactant: Oc1cccc(Oc2ncc(Cl)cn2)c1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1cc(C)nc(Oc2cccc(Oc3ncc(Cl)cn3)c2)n1
Yield: 39.7 %

Procedure:
A mixture of 2-(3-hydroxyphenoxy)-5-chloropyrimidine (2.22 g), 2-chloro-4,6-dimethylpyrimidine (1.43 g), isobutyl methyl ketone (25 ml) and anhydrous potassium carbonate (1.52 g) was heated under reflux for a period of 48 hours. The reaction mixture was diluted with water and the aqueous mixture was extracted with chloroform. The chloroform extract was dried and the solvent was removed by distillation under reduced pressure to give a pale yellow solid. The solid was recrystallised from ethanol to give the title compound (1.3 g), m.p. 142° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].O=[C:10]([CH3:18])[CH2:11][CH2:12][C:13](OCC)=[O:14]>O>[O:5]=[C:4]1[CH2:3][N:2]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2([CH3:18])[NH:6]1
Reactant: NCC(N)=O
Reactant: CCOC(=O)CCC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC12CCC(=O)N1CC(=O)N2
Yield: 21 %

Procedure:
To a solution of glycinamide hydrochloride (18.4 g, 0.166 mol) in water (200 ml), adjusted to pH 9.5 with 10% sodium hydroxide (about 60 ml), ethyl 4-oxopentanoate (20 g, 0.139 mol) was added. The solution was refluxed for 24 hours. After cooling the solvent was evaporated under vacuum and the residue was chromatographed over silica gel (dichloromethane-methanol 9:1) to afford 4.5 g (21%) of the title compound, m.p. 187°-189° C. NMR (CDCl3): deltaH =4.17 and 3.53 (ABq, J=16 Hz, 2H, NCH2CO), 1.5 (s, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=154 (M+), 139 (M-CH3)+, 111 (M-CONH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=[CH2:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][SiH:18]([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][Si:18]([CH3:25])([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: C[SiH](C)c1ccccc1
Agent: O=[Pt]=O
Product: CC(C)(C)OC(=O)N1[C@@H](CC[Si](C)(C)c2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(S)-2,2-Dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester (750 mg; CAS 133625-87-3) was dissolved in dimethylphenylsilane (25 ml), platinum(IV)-oxide (187 mg) was added and the mixture was stirred overnight at room temperature. The catalyst was filtered off and the filtrate was evaporated in vacuo. The crude product was purified by column chromatography (SiO2; heptane/ethyl acetate=4:1) to give (S)-4-[2-(dimethyl-phenyl-silanyl)ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.14 g, 95%) as colourless oil, which was used directly for the next step.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[CH3:28]>CS(C)=O.O>[CH3:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]1=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: O=c1[nH]cccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(C(F)(F)F)c1=O
Temperature: 80 °C

Procedure:
2.5 g (15.3 mmol) of 3-(trifluoromethyl)pyridin-2(1H)-one are dissolved in 40 ml of dimethyl sulfoxide and admixed at room temperature with 2.58 g (22.9 mmol) of potassium tert-butoxide. The suspension is stirred at room temperature for 30 min, before 2.6 g (16.9 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are added and the reaction solution is heated to 80° C. for 20 h. It is diluted cautiously with water. The solution is extracted repeatedly with dichloromethane. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in acetonitrile and purified by preparative HPLC with a gradient of water and acetonitrile. The product fractions are combined and concentrated to dryness under reduced pressure. This affords 1.87 g (41% of theory) of the desired product.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][CH2:12][C@H:13]([O:18][CH2:19][CH:20]=[N:21][OH:22])[CH2:14][CH:15]=[CH:16][CH3:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>ClCCl>[CH2:4]([O:11][CH2:12][C@@H:13]1[O:18][CH2:19][C:20]2=[N:21][O:22][C@@H:16]([CH3:17])[C@@H:15]2[CH2:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC=CC[C@H](COCc1ccccc1)OCC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1ON=C2CO[C@@H](COCc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 6.6 L) was slowly added to a solution of 2-{[(2R)-1-(benzyloxy)hex-4-en-2-yl]oxy}-N-hydroxyethanimine (C12) (660 g, 2.51 mol) and triethylamine (19 g, 0.19 mol) in dichloromethane (6.6 L) at 25° C. After completion of the addition, the reaction mixture was stirred at 25° C. for 30 minutes. The organic layer was washed with water (3×3 L), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Eluent: ethyl acetate in petroleum ether) provided (3S,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C13) as a white solid. Yield: 90 g, 0.34 mol, 14%. The indicated relative stereochemistry of compound C13 was assigned based on NOE studies, which revealed interactions of the methine proton on carbon 3a with both the methine proton on carbon 5 and the protons of the methyl group on carbon 3. LCMS m/z 261.9 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.24-7.39 (m, 5H), 4.69 (d, J=13.7 Hz, 1H), 4.57 (AB quartet, JAB=12.2 Hz, ΔνAB=13.8 Hz, 2H), 4.13-4.25 (m, 2H), 3.62-3.70 (m, 1H), 3.55 (dd, half of ABX pattern, J=10, 6 Hz, 1H), 3.47 (dd, half of ABX pattern, J=10, 4 Hz, 1H), 2.93 (br ddd, J=11, 11, 7 Hz, 1H), 2.11 (br dd, J=12.6, 6.8 Hz, 1H), 1.45-1.56 (m, 1H), 1.45 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cc1cccc(O)c1
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(C)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and m-cresol: 1H-NMR (CDCl3) δ 7.89 (1H, d, J=2.8 Hz), 7.40 (1H, dd, J=8.8, 2.8 Hz), 7.21 (1H, t, J=7.9 Hz), 6.96–6.87 (2H, m), 6.81–6.72 (2H, m), 3.83 (3H, s), 2.83 (3H, s).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[C@@H:6]1[C:17](O)=O)(=O)C.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>Cl>[C:20]([C:24]1[CH:29]=[CH:28][C:27]2[NH:30][C:17]([C@@H:6]3[C@H:5]([OH:4])[CH2:9][CH2:8][NH:7]3)=[N:31][C:26]=2[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: Cl
Product: CC(C)(C)c1ccc2[nH]c([C@H]3NCC[C@H]3O)nc2c1
Temperature: 60 °C

Procedure:
The title compound was prepared according to Method 4 Steps 1 and 2 using (3R)-3-acetoxy-1-(tert-butoxycarbonyl)-L-proline (Preparation 47) and 4-tert-butyl-1,2-diaminobenzene. The residue was dissolved in 6N HCl (5 mL) at 0° C. and then heated to 60° C. for 4 hours. The reaction was cooled, concentrated in vacuo and purified through an SCX cartridge (47 mg, 66%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:9].[C:10]1([PH+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Br-:9].[CH2:1]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][P+:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: OCc1ccccc1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: [Br-]
Product: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
15.15 g (70.7 mmol) of the benzyl alcohol IIIa and 21.86 g (63.7 mmol) of triphenyl-phosphonium hydrobromide in 240 ml of acetonitrile are heated at reflux for 5 hours. The solvent is evaporated under reduced pressure, and diethyl ether is then added. The solid is filtered and dried under reduced pressure.