Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH:6]=[O:7]>CO.CCCCC>[Cl:3][C:4]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH2:6][OH:7]
Reactant: Cc1cc(F)c(C=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CO
Product: Cc1cc(F)c(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Sodium borohydride (1.42 g, 37.5 mmol) was added in portions to an ice-cooled solution of 2-chloro-6-fluoro-4-methylbenzaldehyde (6.25 g, 38.2 mmol) in methanol (56 mL); once addition was complete the reaction was allowed to warm rt with stirring over 1 h and then concentrated in vacuo. The residue was partitioned between ether and saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous re-extracted with ether. The organic layers were combined, washed with H2O, dried with MgSO4 and concentrated in vacuo to yield the crude product as an oil. This oil was diluted with pentane, cooled and stirred which resulted in a white solid. Filtration and drying in vacuo yielded the title compound (5.10 g, 29.2 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C@H:10]([CH3:33])[C@@H:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:34]1[C@@H:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:37]([C:46]([O-])=[O:47])[O:36][C:35]1([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:49]([O:51][CH2:52][CH3:53])=[O:50].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)(Cl)Cl.O>[C:1]([O:5][C:6]([CH2:8][N:9]([C@H:10]([CH3:33])[C@@H:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:46]([C@H:37]1[C@H:38]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[O:34][C:35]([C:49]([O:51][CH2:52][CH3:53])=[O:50])([C:54]([O:56][CH2:57][CH3:58])=[O:55])[O:36]1)=[O:47])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)[O-])[C@H](C(=O)OC(C)(C)C)O1
Reactant: C[C@@H](NCC(=O)OC(C)(C)C)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)OC(C)(C)C)[C@H](C(=O)N(CC(=O)OC(C)(C)C)[C@H](C)[C@H](CCc2ccccc2)c2ccc(Oc3ccccc3)cc2)O1
Reaction time: 1 h
Yield: 95 %

Procedure:
860 mg of N-(tert-butoxycarbonylmethyl)-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}amine obtained in Example 50, 1.04 g of 5-tert-butyl 2,2-diethyl (4R,5R)-1,3-dioxolane-2,2,4,5-tetracarboxylate obtained in Example 68, and 2.02 ml of triethylamine, were dissolved in 20 ml of chloroform, and a solution of 816 mg of 2-chloro-1,3-dimethylimidazolinium chloride in 10 ml of chloroform, was added under cooling with ice, followed by stirring at the same temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The extract solution was washed with a saturated sodium chloride aqueous solution and then, dried over anhydrous sodium sulfate. The drying agent was filtered off and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 1.45 g (yield: 95%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[O:10]2)=[C:5]([CH3:16])[O:4][N:3]=1.CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](=[O:19])[CH2:14][CH2:13][CH2:12][C:11]([OH:15])=[O:10])=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: Cc1noc(C)c1CCC1CCCC(O)O1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Product: Cc1noc(C)c1CCC(=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dimethyl-4-(6-hydroxytetrahydropyran-2-ylethyl)-isoxazole, prepared as described above in 600 ml. of acetone was cooled in an ice bath as 400 ml. of Jones reagent was added dropwise over a 1.0 hr. period. The resulting suspension was stirred at room temperature overnight. Saturated sodium bisulfite solution was added to destroy the excess oxidizing agent and most of the acetone was removed at reduced pressure. The residue was diluted with water, saturated with sodium chloride, and extracted with ethyl acetate. The ethyl acetate solutions were washed with brine and then with excess saturated aqueous sodium bicarbonate solution. The sodium bicarbonate solutions were washed with ether, acidified with 3N hydrochloric acid, saturated with sodium chloride, and extracted with ethyl acetate. The ethyl acetate solutions were washed with brine and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a pale yellow resin. Crystallization of this material from ether gave two crops of racemic 7-(3,5-dimethyl-4-isoxazolyl)-5-oxo-heptanoic acid as a fine white powder, m.p. 61.5°-63.5°.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1.C[O:19][C:20](OC)(OC)[CH3:21].[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:41]3[CH:40]=[C:39]4[CH2:42][CH2:43][C@@H:44]5[C@@H:49]([C@@:38]4([CH3:60])[CH2:37][C:36]=3[CH:35]=[N:34]2)[C@@H:48]([OH:50])[CH2:47][C@:46]2([CH3:59])[C@:51]([C:55](=[O:58])[CH2:56][OH:57])([OH:54])[CH2:52][CH2:53][C@@H:45]52)=[CH:29][CH:28]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O.CCOC(C)=O>[C:20]([O:54][C@@:51]1([C:55](=[O:58])[CH2:56][OH:57])[C@:46]2([CH3:59])[C@H:45]([C@H:44]3[C@H:49]([C@@H:48]([OH:50])[CH2:47]2)[C@@:38]2([CH3:60])[CH2:37][C:36]4[CH:35]=[N:34][N:33]([C:30]5[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=5)[C:41]=4[CH:40]=[C:39]2[CH2:42][CH2:43]3)[CH2:53][CH2:52]1)(=[O:19])[CH3:21]
Reactant: COC(C)(OC)OC
Reactant: C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3CCC4=Cc5c(cnn5-c5ccc(F)cc5)C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.2 %

Procedure:
According to the literature (Chem. Pharm. Bull. 2006, 54(11), 1567-1570) pyridine 4-methylbenzenesulfonate (0.034 g, 0.14 mmol) and 1,1,1-trimethoxyethane (0.136 ml, 1.06 mmol) were added to a solution of 1-[(1R,3aS,3bS,10aR,10bS,11S,12aS)-7-(4-fluorophenyl)-1,11-dihydroxy-10a,12a-dimethyl-1,2,3,3a,3b,4,5,7,10,10a,10b,11,12,12a-tetradecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl]-2-hydroxyethanone (Steroids 2003 (68) 177-191) (0.34 g, 0.71 mmol) in DCM (15 ml). The mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, the obtained residue was dissolved in acetone (10 ml) and 4-methyl benzenesulfonic acid hydrate (0.21 g, 1.10 mmol) dissolved in water (10 ml) was added while cooling in an ice-bath. The mixture was stirred for 60 min. at the same temperature followed by the addition of sat. NaHCO3 solution (15 ml) and subsequent extraction with EtOAc (30 ml). The organic layer was washed with brine, dried and purified on a preparative HPLC column (CH3CN/water) and the product containing fractions were freeze-dried to give 60 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:16][CH2:15][CH2:14][C@@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:16][CH2:15][CH2:14][C@@:13]([CH2:23][C:24]([CH3:26])=[CH2:25])([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)[CH:33]=[CH:32][N:31]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: C=C(C)C[C@@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=C(C)C[C@@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccnc(OC)c3)cc2)C(=O)O1

Procedure:
(R)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-7-(2-methylallyl)-7-phenyl-1,3-oxazepan-2-one and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following conditions analogous to those described in Example 6 using PdCl2(dppf) as catalyst. tR=2.28 min, m/z 457 (M+1). 1H NMR (CD3OD) δ 8.13 (m, 2H), 7.83 (d, 1H), 7.71 (d, 2H), 7.49 (t, 3H), 7.33 (t, 2H), 7.24 (m, 2H), 7.06 (d, 1H), 5.41 (q, 1H), 4.56 (s, 1H), 3.85 (d, 3H), 3.17-2.99 (m, 2H), 2.39 (dt, 1H), 2.09 (m, 1H), 1.45 (s, 3H), 1.38 (d, 3H).
Reaction SMILES: OCCC[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[NH+]1C=CC=CC=1.[C:16]([CH2:18][CH2:19][O:20][P:21](=[O:24])([OH:23])[OH:22])#N>>[NH:7]1[CH:8]=[CH:9][N:5]=[C:6]1[CH2:16][CH2:18][CH2:19][O:20][P:21](=[O:22])([OH:24])[OH:23]
Reactant: N#CCCOP(=O)(O)O
Reactant: OCCCn1ccnc1
Agent: c1cc[nH+]cc1
Product: O=P(O)(O)OCCCc1ncc[nH]1

Procedure:
Using 0.13 g of the purified 1-(3-hydroxypropyl)imidazole and 2 ml of 2-cyanoethylphosphoric acid pyridinium solution (1 mmol/ml), and subsequently following the same processes as in Example 1, 0.2 g of crude 3-imidazolylpropylphosphoric acid was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[CH3:31][O:32][CH2:33][C:34]([NH:21][C:17]1[CH:16]=[C:15]([O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:20]=[CH:19][N:18]=1)=[O:35]
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Reactant: COCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a suspension of 6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-amine (350 mg, 1.24 mmol) in DCM (10.0 mL) and DIPEA (433 μL, 2.48 mmol) at 0° C. was added 2-methoxyacetyl chloride (170 μL, 1.860 mmol). The mixture was warmed to RT and after 3 hr the reaction was quenched by the addition of a solution of NH3 in MeOH (7M, 20 mL) and after a further 10 min was evaporated in vacuo. The residue was partitioned between DCM (30 mL) and saturated aq NaHCO3 solution (30 mL) and the organic layer was separated and washed with brine (30 mL) and then dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, MeOH in DCM, 0-100%, gradient elution) to furnish the title compound as a yellow solid (400 mg, 86%); Rt 4.60 min (Method 1 basic); m/z 355 (M+H)+ (ES+).
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[C:15](=O)[CH2:14][CH2:13][C:12]3=O)[CH:9]=2)[CH:4]=[CH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[N:11]1([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][NH:2]3)=[CH:6][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cn1ccc2ccc(N3C(=O)CCC3=O)cc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1cc2ccc(N3CCCC3)cc2[nH]1

Procedure:
1-(1-Methyl-1H-indol-6-yl)-pyrrolidine-2,5-dione (3.8 g, 17.7 mmol) in tetrahydrofuran (75 ml) was treated with lithium aluminum hydride in tetrahydrofuran (88 ml, 1.0 M, 88 mmol) for 2 hours at room temperature. The mixture was cooled and treated with aqueous sodium sulfate. The mixture was extracted with ether and the organic layer was concentrated. Chromatography of the crude product over silica gel with 70% hexane/ethyl acetate gave 6-pyrrolidin-1-yl-1H-indole as a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12]([C:18]#[N:19])=[N:13][CH:14]=[C:15](F)[CH:16]=1.[NH2:20][C@H:21]1[C@@H:26]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:25][CH2:24][S:23](=[O:36])(=[O:35])[CH2:22]1>CN1C(=O)CCC1.O>[Br:10][C:11]1[CH:16]=[C:15]([NH:20][C@H:21]2[C@@H:26]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:25][CH2:24][S:23](=[O:36])(=[O:35])[CH2:22]2)[CH:14]=[N:13][C:12]=1[C:18]#[N:19]
Reactant: N#Cc1ncc(F)cc1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS(=O)(=O)C[C@H]1N
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCS(=O)(=O)C[C@H]1Nc1cnc(C#N)c(Br)c1
Temperature: 150 °C

Procedure:
A mixture of Hunig's base (2.69 ml, 15.4 mmol), 3-bromo-5-fluoropyridine-2-carbonitrile (1.55 g, 7.69 mmol), tert-butyl rel-[(3S,4S)-3-amino-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]carbamate (2.51 g, 9.50 mmol) in NMP (8 ml) was heated to 150° C. for 30 minutes. The reaction mixture was diluted with water (50 mL) and stirred. The reaction mixture was filtered, and the collected solids were washed with cold water. The solids were dried under reduced pressure to afford tert-butyl rel-{(3S,4S)-3-[(5-bromo-6-cyanopyridin-3-yl)amino]-1,1-dioxidotetrahydro-2H-thiopyran-4-yl}carbamate. MS ESI calc'd. for C16H22BrN4O4S [M+H]+ 445 and 447. found 445 and 447.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][S:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35])(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[S:29]([CH3:28])(=[O:31])=[O:30])[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: CS(=O)(=O)c1ccccc1CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3S(C)(=O)=O)ncc2[N+](=O)[O-])CC1
Reaction time: 24 h
Yield: 69.1 %

Procedure:
{4-[(2-Chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) was dissolved in DMF (3 mL). 2-Methanesulfonyl-benzylamine hydrochloride (115 mg, 0.52 mmol) and diisopropylethylamine (0.14 mL, 0.78 mmol) were added sequentially. After 24 h, the reaction was partitioned between water (10 mL) and DCM (10 mL). The organic layer was washed with 5% AcOH (aq), saturated Na2CO3 and water, dried over MgSO4, filtered and concentrated. Chromatography (silica, 0-15% MeOH in DCM; Rf=0.3 10% MeOH in DCM) yielded 96 mg of (4-{[2-(2-methanesulfonyl-benzylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester as a pale yellow solid, m/z 535.7 [M+1]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].Cl[CH:13](C)[CH2:14][NH2:15].Cl>O.CO>[NH2:15][CH2:14][CH2:13][CH2:2][S:1][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3]
Reactant: CC(Cl)CN
Reactant: c1ccc2scnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NCCCSc1ccccc1N
Temperature: 70 °C
Reaction time: 3 h

Procedure:
270 parts of benzothiazole and 160 parts of sodium hydroxide are boiled under reflux for 3 hours in 400 parts of water. After cooling to 70° C., 250 parts of methanol are added, followed by the dropwise addition over a period of 2 hours at 70° C. of a solution of 260 parts of 2-chloropropylamine·HCl in 500 parts of water. After stirring for another 3 hours at 100° C., the mixture is cooled and a solution of 100 parts of sodium hydroxide in 200 parts of water is added to it. The organic phase is separated off, the aqueous phase is washed twice with 200 parts of toluene and the combined organic phases are concentrated by evaporation, leaving 346 parts of 2-(3-aminopropylthio)-aniline in the form of a yellowish liquid boiling at 130° C./0.04 mm.
Reaction SMILES: O[CH:2]([CH3:17])[C:3]#[C:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:37]([C:44]([NH:46][O:47][C:48]([O:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:49])=[O:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>[O:50]([C:48]([O:47][N:46]([CH:2]([CH3:17])[C:3]#[C:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:6]1)[C:44]([O:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:45])=[O:49])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC(O)C#C[C@H]1CC[C@H](c2ccc(F)cc2)O1
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C#C[C@H]1CC[C@H](c2ccc(F)cc2)O1)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
trans-2-(3-Hydroxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (205, 210 mg, 0.89 mmol), triphenylphosphine (288 mg, 1.1 mmol) and N,O-bis(phenoxycarbonyl)hydroxylamine (283 mg, 1.1 mmol) were dissolved in dry THF (5 mL). The solution was cooled to 0° C. under dry argon, and diisopropylazodicarboxylate (216 mL, 1.1 μmol) was added dropwise. Stirring was continued for 1 hour at the same temperature. The solvent was evaporated and the residue was purified via flash column chromatography (eluent, 30% ethyl acetate in hexane) to yield 250 mg (57%) of trans-2-{3-(N-phenoxycabonyloxy-N-phenoxycarbonyl-amino)-but-1-ynyl}-5-(4-fluorophenyl) tetrahydrofuran (206). 1H-NMR (CDCl3) δ 7.15-7.45 (12H, m), 7.02 (2H, t, J=8.6 Hz), 5.32 (1H, q J=7.0 Hz), 5.07 (1H, t, J=6.8 Hz), 4.96 (1H, t, J=5.7 Hz), 2.25-2.50 (2H, m), 2.05-2.20 (1H, m), 1.70-1.85 (1H, m), 1.66 (3H, d, J=7.0 Hz).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][O:22][C:23](=[O:33])[CH:24]([NH2:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:32][CH:24]([C:23]([O:22][CH3:21])=[O:33])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: COC(=O)C(N)Cc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COC(=O)C(Cc1ccccc1)NC(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 2-amino-3-phenyl-propionic acid methyl ester via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H25NO7 [M+H]+: 416.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].Br[CH2:9][C:10]([OH:12])=[O:11]>C1COCC1>[CH2:3]([O:7][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH:5]=[CH2:6]
Reactant: O=C(O)CBr
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCOCC(=O)O
Reaction time: 0.08 h
Yield: 126.8 %

Procedure:
To 480 mg of NaH (50% in mineral oil, ˜20 mmol) in 10 ml of abs. THF was added at 0° 721 mg of 3-buten-1-ol (10 mmol) and the mixture stirred for 5 min. (H2-evolution). 1.39 g of bromo-acetic acid (10 mmol), dissolved in 10 ml of THF, was then added and the mixture kept for additional 5 min. at 0° and for 2 h at ambient temperature. Pouring onto crashed ice/HCl dil., twofold extraction with AcOEt, washing with brine, drying over natrium sulfate and evaporation of the solvents afforded 1.65 g of the title compound, contaminated with mineral oil, but sufficiently pure for the next step.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([N:10]([CH3:19])[C:11]1([CH2:14][C:15](OC)=[O:16])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[OH:16][CH2:15][CH2:14][C:11]1([N:10]([CH3:19])[C:8](=[O:9])[O:7][C:3]([CH3:4])([CH3:6])[CH3:5])[CH2:12][CH2:13]1
Reactant: COC(=O)CC1(N(C)C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1(CCO)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Over 20 minutes, 20 ml of 2M lithium borohydride in tetrahydrofuran is poured, at 20° C., into a mixture containing 4.86 g of the product obtained in Step 4 and 20 ml of tetrahydrofuran. After stirring for 20 hours at ambient temperature and then for 1 hour at reflux, the mixture is cooled to 5° C. and then hydrolysed using a mixture containing 8 ml of water and 4 ml of 10% aqueous sodium carbonate solution. The aqueous phase is extracted several times with ether. After customary treatment, chromatography of the residue over silica gel (CH2Cl2/tetrahydrofuran: 98/2) allows the expected product to be isolated (liquid).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O([Si:20]([CH3:23])([CH3:22])[CH3:21])S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>CCOCC.ClCCl>[CH3:11][O:10][C:8]([O:9][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=Cc1ccccc1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Cool methyl phenylacetate (1.80 mL, 12.5 mmol) to 0° C. using and ice/water bath. Add dropwise and with vigorous stirring, a solution of trimethylsilyl triflate (2.70 mL, 4 mmol) and triethylamine (1.95 mL, 14 mmol) in dry ether (25 mL). When the addition is complete, warm slowly to ambient temperature. After 4.5 hours, cool in an ice/bath to obtain a heavier reddish oil. Remove the reddish oil by syringe. Evaporate the ether under high vacuum at 0° C. to obtain a residue and dissolve the residue in dichloromethane (25 mL) to give the title compound as a solution in dichloromethane which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C@@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>O1CCOCC1>[NH2:21][C@@H:19]([CH3:20])[CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8]
Reactant: CCOP(=O)(CCOCCOCCOC[C@H](C)NC(=O)OC(C)(C)C)OCC
Solvent: C1COCCO1
Product: CCOP(=O)(CCOCCOCCOC[C@H](C)N)OCC

Procedure:
A solution of (S)-tert-butyl (1-(2-(2-(2-(diethoxyphosphoryl)ethoxy)ethoxy)ethoxy)propan-2-yl)carbamate (1 eq) in 4N HC1/dioxane (0.4 M) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated en vaccuo to give the title product as a colorless viscous oil.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]1[C:14]([O:21][CH3:22])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C=O)C>[F:10][C:9]1[C:2]([O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]=[O:17])[C:14]=2[O:21][CH3:22])=[C:3]([CH:6]=[CH:7][C:8]=1[CH3:11])[C:4]#[N:5]
Reactant: COc1c(O)cccc1C=O
Reactant: Cc1ccc(C#N)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1Oc1c(C#N)ccc(C)c1F
Yield: 30 %

Procedure:
2,3-Difluoro-4-methylbenzonitrile (0.21 g, 1.4 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.21 g, 1.4 mmol) and cesium carbonate (0.45 g, 1.4 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 18 h. The reaction mixture was cooled, poured into 0.1N sodium hydroxide-solution and extracted with diethyl ether. The ether layer was separated, washed with 0.1N sodium hydroxide solution (2×), water (3×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo, and purified by chromatography to yield 3-fluoro-2-(3-formyl-2-methoxyphenoxy)-4-methylbenzonitrile (0.12 g, 31%) as a colourless glass.