Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:27])=[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:35]([CH3:41])([CH3:40])[C:36](OC)=[O:37]>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:27][C:35]([CH3:41])([CH3:40])[C:36](=[O:37])[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[C:11]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2O)CC1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Oc3ccc(Cl)cc32)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
To a N,N-dimethylformamide solution (23 ml) of tert-butyl 4-[(5-chloro-2-hydroxyphenyl)amino]piperidine-1-carboxylate (1.15 g) were added at room temperature cesium carbonate (5.73 g) and methyl 2-bromo-2-methylpropanoate (1.27 g), followed by stirring at 140° C. for 2 hours. After the reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(6-chloro-2,2-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)piperidine-1-carboxylate.
Reaction SMILES: NC1C=CC(O[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]C2)=CC=1.[CH2:22]([N:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([C:36]([OH:38])=O)=[CH:34][N:35]=2)[CH:28]=[N:27]1)[CH:23]([CH3:25])[CH3:24].C(OC([N:49]1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[CH2:22]([N:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([C:36]([NH:49][C@H:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]3)=[O:38])=[CH:34][N:35]=2)[CH:28]=[N:27]1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Cn1cc(-c2ncc(C(=O)O)s2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: CC(C)Cn1cc(-c2ncc(C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)s2)cn1

Procedure:
The title compound was prepared as described in Example 1A, substituting (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 2-(1-isobutyl-1H-pyrazol-4-yl)thiazole-5-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[N:19]2[CH2:22][C:21](=[CH:23][S:24]([CH2:27][C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=3)[C:31](O)=[O:32])(=[O:26])=[O:25])[CH2:20]2)=[CH:14][CH:13]=1>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)[N:19]2[CH2:22][C:21](=[CH:23][S:24]([CH2:27][C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=3)[C:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:32])(=[O:26])=[O:25])[CH2:20]2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: NCCCN1CCOCC1
Solvent: ClCCl
Product: O=C(NCCCN1CCOCC1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reaction time: 1.5 h

Procedure:
0.0388 cm3 of N-(3-aminopropyl)morpholine is added, at the same temperature, to a suspension of 150 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid activated on TFP resin (165 μM) in 3 cm3 of dichloromethane, pre-stirred for 90 minutes at a temperature close to 20° C. The suspension is stirred at a temperature close to 20° C. for 22 hours and then filtered on sintered glass. The solid residue is rewashed with twice 1.5 cm3 of dichloromethane. The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40° C. 60 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-morpholin-4-ylpropyl)benzamide are thus obtained in the form of a pale yellow foam.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]([NH:10][NH:11][C:12]2[N:13]=[C:14]3[CH:20]=[CH:19][N:18]([S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[C:15]3=[N:16][CH:17]=2)=O)[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)[CH3:2].S(Cl)(Cl)=O.Cl.CCOCC>O1CCOCC1>[CH2:1]([C@H:3]1[CH2:4][NH:5][CH2:6][C@H:7]1[C:8]1[N:13]2[C:14]3[CH:20]=[CH:19][N:18]([S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[C:15]=3[N:16]=[CH:17][C:12]2=[N:11][N:10]=1)[CH3:2]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC[C@H]1CNC[C@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 70 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of (cis)-tert-butyl 3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyrrolidine-1-carboxylate (9.4 g, 16.41 mmol) in 1,4-dioxane (150 mL), TEA (7.00 mL, 50.2 mmol) and thionyl chloride (1.80 mL, 24.6 mmol) were each added sequentially in one portion to the solution. The reaction was heated at about 70° C. for about 18 h. The solvent was removed under reduced pressure. A solution of HCl (4 M in 1,4-dioxane, 41.0 mL, 164 mmol) was added in one portion and the reaction was stirred for about 3 h. Et2O (100 mL) was added and the solid was filtered. The solids were combined with the mother liquor and the solvent was removed under reduced pressure. The solid was partially dissolved in EtOAc (650 mL) and washed with aqueous saturated NaHCO3 (150 mL). An emulsion formed and was fitered through Celite® washing with EtOAc. The solid on top of the Celite® layer was product. The solid was scraped off of the Celite® and dissoved in a solution of 10% MeOH in DCM (150 mL). The organic layer was washed with water (2×30 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (4×150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (5.88 g, 80%) as a brown foam: LC/MS (Table 1, Method a) Rt=1.55 min; MS m/z: 411 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([Si:17]([CH3:20])([CH3:19])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCNCC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 173.2 %

Procedure:
To a solution of 4-hydroxypiperidine (2.00 g, 9.89 mmoles) in CH2Cl2 (30 mL) is added 1H-imidazole (2.69 g, 39.55 mmoles) followed by t-butyldimethylchlorosilane (3.58 g, 23.73 mmoles) and the reaction mixture is stirred at room temperature. After 12 hours, the reaction mixture is washed with water, saturated solution of NaHCO3, and brine. The organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 100% CH2Cl2 to 10% 7N ammonia in MeOH/90% CH2Cl2 to afford the title compound (3.69 g, 86.3%). Mass spectrum (m/z): 216.2 (M+1).
Reaction SMILES: C(N(CC)C1C=C2C([C@H](N(C3C=CC(N(CC)CC)=CC=3)C(=O)C)C[C@H](C)N2C(=O)C2C=CC(N(C)C)=CC=2)=CC=1)C.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]([C@H:54]2[C:63]3[C:58](=[CH:59][C:60]([N:64]4[CH2:69][CH2:68]O[CH2:66][CH2:65]4)=[CH:61][CH:62]=3)[N:57]([C:70](=[O:80])[C:71]3[CH:76]=[CH:75][C:74]([N:77]([CH3:79])[CH3:78])=[CH:73][CH:72]=3)[C@@H:56]([CH3:81])[CH2:55]2)[C:51](=[O:53])[CH3:52])=[CH:46][CH:45]=1.C(NCC)C.N1CCOCC1>>[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([N:50]([C@H:54]2[C:63]3[C:58](=[CH:59][C:60]([N:64]([CH2:65][CH3:66])[CH2:69][CH3:68])=[CH:61][CH:62]=3)[N:57]([C:70](=[O:80])[C:71]3[CH:72]=[CH:73][C:74]([N:77]([CH3:78])[CH3:79])=[CH:75][CH:76]=3)[C@@H:56]([CH3:81])[CH2:55]2)[C:51](=[O:53])[CH3:52])=[CH:48][CH:49]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2cc(N3CCOCC3)ccc21
Agent: CCN(CC)c1ccc(N(C(C)=O)[C@@H]2C[C@H](C)N(C(=O)c3ccc(N(C)C)cc3)c3cc(N(CC)CC)ccc32)cc1
Solvent: CCNCC
Solvent: C1COCCN1
Product: CCN(CC)c1ccc2c(c1)N(C(=O)c1ccc(N(C)C)cc1)[C@@H](C)C[C@H]2N(C(C)=O)c1ccc(Cl)cc1

Procedure:
(±)-Cis-N-[7-diethylamino-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-diethylamino-phenyl)-acetamide was made in the same way as (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-dimethylamino-benzoyl)-2-methyl-7-morpholin-4-yl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide except diethylamine was substituted for morpholine. The reaction was non-selective and yielded (±)-cis-N-(4-chloro-phenyl)-N-[7-diethylamino-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide in addition to the titled compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]=O)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[N:31][OH:32])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21][CH3:22])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C=NO)=C(C(=O)OCC)C1c1ccccc1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of diethyl 2-methyl-4-(-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.6 g), hydroxylamine hydrochloride (495 mg) and sodium acetate (691 mg) in acetic acid (20 ml) was stirred at room temperature for an hour to form diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. To the reaction mixture was added acetic anhydride (2.18 ml) and the mixture was heated at 110° C. for 3.5 hours with stirring. Acetic acid was distilled off under reduced presssure from the reaction mixture and the resultant residue was adjusted to pH 8 with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, and saturated aqueous sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness. The resultant oil (2.88 g) was chromatographed on a column of silica-gel (72 g), and eluted with a mixture of benzene and ethyl acetate (10:1, v/v) to give an oil (1.6 g), which was triturated with diisopropyl ether (3 ml) to give crystalline powder (1.3 g). Recrystallization from a mixture (20 ml) of diisopropyl ether and ethanol (15:1, v/v) gave pure crystals of diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.03 g), mp 120° to 127° C.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[F:13][C:14]([F:27])([F:26])[C:15]([F:25])([F:24])[C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>>[O:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=[C:4]1[C:1](=[O:3])[CH2:2][C:17](=[O:18])[C:16]([F:22])([F:23])[C:15]([F:24])([F:25])[C:14]([F:27])([F:26])[F:13]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: CCOC(=O)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(CC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1cc2ccccc2o1

Procedure:
The compound was synthesized according to example 1 using 2-acetylbenzofuran and ethyl heptafluorobutyrate as starting materials. The product was crystallized from petroleum ether. 1H NMR (CDCl3): 6.74 (s, 1 H); 7.35 (ddd, 1H, J=0.9 & 7.2 & 8.0 Hz); 7.52 (ddd, 1H, J=1.3 & 7.2 & 8.4 Hz); 7.58-7.61 (m, 1 H); 7.68 (d, 1H, J=0.9 Hz); 7.71-7.74 (m, 1 H). IR (film): 1614 (C═O); 1232 (C—F).
Reaction SMILES: Br[C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].[CH3:13][O-:14].[Na+]>>[CH3:13][O:14][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12]
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Reactant: C[O-]
Agent: [Na+]
Product: COc1c(O)cc(C(=O)O)cc1O
Yield: 45 %

Procedure:
Treatment of 4-bromo-3,5-dihydroxybenzoic acid (23.3 g, 0.1 mole) with sodium methoxide (18.5 g, 0.8 g atom) in an analogous procedure to that of Example 9 with a 9 hour reflux yielded 12 g (theory 18.4 g) of a white solid, m.p 238°-42° C. NMR showed this to be 45% title product and 55% starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][C:9]=2[C:10]=1[C:11](O)=[O:12])=[O:5].C(Cl)CCl.C1C=CC2N(O)N=[N:40]C=2C=1.[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][C:9]=2[C:10]=1[C:11]([NH2:40])=[O:12])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: Cc1cccc(-c2ccc3c(C(=O)O)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccc3c(C(N)=O)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 2-(2,4-Dichloro-benzoyl)-6-m-tolyl-benzofuran-3-carboxylic acid from step 6 (61.2 mg, 0.14 mmol, 1 eq) in anhydrous THF (3 mL) solution were added EDC (60.0 mg, 0.31 mmol, 2.2 eq) and HOBt (50.0 mg, 0.37 mmol, 2.6 eq). The reaction mixture was stirred at rt for 1 h. A 30% aq. NH4OH solution (0.5 mL) was added to the reaction mixture and stirring was continued for 15 h. The reaction mixture was poured into EtOAc (10 mL). The organic layer were washed with 1N NaOH (5 mL), 1N HCl (5 mL), brine (5 mL). The organic layer was dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by pre-TLC (10% Acetone/DCM) to afford an yellow solid (46.2 mg, 78%) as product. 1H-NMR (CDCl3): δ 9.39 (broad, NH, 1H), 8.58 (d, J=8.3 Hz, 1H), 7.68 (dd, J=1.5, 8.3 Hz, 1H), 7.63 (s, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.43-7.40 (m, 3H), 7.32 (t, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.01 (broad, NH, 1H), 2.42 (s, 3H); LC-MS (MH+=424/426).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:19][CH2:18][O:17][CH:16]1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N([CH:32]([CH3:34])[CH3:33])CC)(C)C>C(Cl)Cl>[C:14]1([C:33]2[CH:32]=[CH:34][CH:21]=[CH:20][CH:25]=2)[CH:15]=[CH:16][C:2]([CH2:1][O:5][C@H:19]2[CH2:18][O:17][C@H:16]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C@@H:15]2[CH2:14][CH2:13][CH:12]=[O:11])=[CH:12][CH:13]=1
Reactant: OCCCC1CCOC1c1cccnc1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCC[C@@H]1[C@@H](OCc2ccc(-c3ccccc3)cc2)CO[C@@H]1c1cccnc1
Temperature: -60 °C

Procedure:
To a solution of 0.48 g (0.00383 mole) of oxalyl chloride in 7 ml of methylene chloride is added dropwise a solution of 0.54 g (0.0067 mole) of dimethylsulfoxide in 4 ml of dichloromethane with stirring at -60° C. After stirring the mixture for another 10 min at -70° C., a solution of 0.95 g (0.00244 mole) of (2S,3S,4R)-4-(biphenyl)-4-ylmethoxy)-3-(3-hydroxyprop-1-yl)-2-(3-pyridyl)tetrahydrofuran in 8 ml of dichloromethane is added dropwise over a period of 10 min. The mixture is stirred at -70° C. for 1 h and 2.48 ml (0.014 mole) of diisopropylethyl amine are added at once. The mixture is allowed to warm up to room temperature, washed with water and brine, dried (MgSO4) and evaporated. The residue is purified by flash chromatography using methylene chloride-methanol-ammonium hydroxide (300:25:1) as eluent to give (2S,3S,4R)-3-[4-(biphenyl-4-ylmethoxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]propanal as oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([CH:12]=[CH:13][C:14]([CH3:17])(O)[CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:18]([O-:21])(=[O:20])C.[Na+]>CN(C)C=O.O>[CH3:15][C:14]([CH:13]=[CH:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:17][C:18]([OH:21])=[O:20]
Reactant: CC(C)(O)C=Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C=Cc1ccccc1)=CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
Dimethylformamide (DMF, anhydrous, 25 mL) was cooled to 0–5° C. and phosphorus oxychloride (16.4 mL) was added dropwise over a period of an hour. The resulting solution was added dropwise to a cooled (0–5° C.) solution of 4-phenyl-2-methyl-3-buten-2-ol (0.14 mol) in 60 mL of anhydrous DMF over a period of an hour. The reaction mixture was then warmed to room temperature, gradually heated up to 80° C., stirred at 80° C. for three hours and cooled to 0–5° C. To the cooled reaction solution was added dropwise a solution of sodium acetate (80 g) in deionized water (190 mL) over a period of two hours. The mixture was then reheated to 80° C., stirred at 80° C. for an additional 10 minutes, cooled down to room temperature and extracted with ether (300 mL) twice. The combined extract was washed with water (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to yield 16.7 g of the desired 3-methyl-5-phenyl-2,4-pentadienal as a liquid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:16][C@@H:17]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[C@@H:20]([S:31][CH3:32])[O:19][C@H:18]1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][CH2:50][OH:51])=[CH:43][CH:42]=2)[CH:34]=1)(=[O:15])[CH3:14]>C(Cl)Cl>[C:13]([O:16][C@@H:17]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[C@@H:20]([S:31][CH3:32])[O:19][C@H:18]1[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([CH2:47][CH2:48][CH2:49][CH2:50][O:51][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:45][CH:46]=2)[CH:34]=1)(=[O:15])[CH3:14]
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCCOS(C)(=O)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Methanesulfonyl chloride (41 μL, 0.53 mmol) and triethylamine (80 μL, 0.58 mmol) were added to a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-hydroxybutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (22, 247 mg, 0.44 mmol) in 5 mL CH2Cl2 and stirred at room temperature for 2 hours. The reaction was quenched with 1N aqueous HCl. The aqueous layer was extracted two times with EtOAc. The combined organic layers were washed with H2O and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide the product 23 (279 mg, 99% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14 (s, 2 H), 7.02-7.11 (m, 3 H), 7.00 (d, J=7.8 Hz, 2 H), 5.33 (dd, J=9.6 Hz, 1 H), 5.21 (dd, J=9.6 Hz, 1 H), 5.12 (dd, J=9.6 Hz, 1 H), 4.48-4.56 (m, 1 H), 4.39 (d, J=9.9 Hz, 1 H), 4.24 (t, J=6.1 Hz, 1 H), 3.93 (d, J=3.8 Hz, 2 H), 2.99 (s, 3 H), 2.62 (t, J=7.2 Hz, 2H), 2.22 (s, 3 H), 2.15-2.20 (m, 3 H), 2.10 (s, 3 H), 2.01 (s, 3 H), 1.70-1.81 (m, 4 H). MS (ES+) [M+NH4]+=654.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH2:15][O:16][CH3:17])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:3].[CH2:18]([OH:20])[CH3:19]>>[CH2:18]([O:20][C:2]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH2:15][O:16][CH3:17])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[NH:3])[CH3:19]
Reactant: CCOC(=O)c1cc(C#N)cc(COC)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cc(COC)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
Hydrogen chloride gas was passed through a solution of ethyl 3-cyano-5-methoxymethyl-benzoate (300 mg, 1.368 mmol) in anhydrous ethanol (15 mL) at 0° C. After 3 h, hydrogen chloride gas was stopped and the reaction vessel was sealed with a septum. After stirring at room temperature overnight, the reaction vessel was cooled to 0° C. and the septum was removed. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford ethyl 3-ethoxycarbonimidoyl-5-methoxymethyl-benzoate (200 mg, 49%).
Reaction SMILES: CCC.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH2:15])[CH2:13][CH3:14])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37])(OCC)=O>O.C(#N)C>[C:28]1(=[O:37])[N:15]([CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[CH2:13][CH3:14])[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCC(N)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCC
Product: CCC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 38.1 %

Procedure:
1-Phthalimido-1-4′-methoxyphenyl)propane. To a stirred solution of 1-(4′-methoxyphenyl)propylamine (2.5 grams, 15.2 mmol) and sodium carbonate (1.74 grams, 16.4 mmol) in a mixture of water (50 milliliters) and acetonitrile (50 milliliters) was added N-carbethoxyphthalimide (3.34 grams, 15.2 mmol). The resulting suspension was stirred for 4.5 hours at room temperature, the acetonitrile was removed in vacuo and a solid formed. The slurry was filtered and the solid was washed with water and air dried to afford 1.73 grams (39%) of crude product as a white powder. The crude product was recrystallized from hexane/ethyl acetate and dried in vacuo (60° C., <1 mm) to afford 1.71 grams (38%) of the product as white crystals: mp 85-86° C.; 1H NMR (DMSO-d6) δ 7.92-7.79 (m, 4H), 7.46-7.28 (m, 2H), 6.97-6.83 (m, 2H), 5.19-5.06 (m, 1H), 3.72 (s, 3H), 2.56-2.13 (m, 2H), 0.87 (t, J=7.3 Hz , 3H); 13C NMR (DMSO-d6) δ 167.8, 1 .5, 134.6, 131.7, 131.0, 128.6, 123.1, 113.7, 55.2, 54.9, 23.8, 11.3. Anal. Calculated for C18H17NO3. Theoretical: C, 73.20; H, 5.80; N, 4.74. Found: C,73.24; H, 5.74, N, 4.86. HPLC 100%.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)(=[O:3])[CH3:2].[C:38](=[O:41])([O-])O.[Na+].ClC(OC[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=O.O>C(OCC)(=O)C>[F:37][C:34]1[CH:35]=[CH:36][C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[C:8]([O:9][CH2:10][CH2:11][O:12][CH:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:41][C@H:38]3[CH2:2][CH2:1][N:4]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH2:5]3)[CH2:17][CH2:16][NH:15][CH2:14]2)[CH:33]=1
Reactant: O=C([O-])O
Reactant: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NCCc1ccc(F)cc1OCCOC1CNCCC1c1ccccc1O[C@H]1CCN(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Analogously to Method A, 2.90 g of tert-butyl 3-{2-[2-(2-acetylaminoethyl)-5-fluorophenoxy]ethoxy}-4-(4-hydroxyphenyl)piperidine-1-carboxylate (Example 223) are reacted. The resulting crude product is subsequently taken up in 50 ml each of ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The reaction mixture is cooled in an ice bath and admixed with 1.00 ml of benzyl chloroformate and subsequently stirred at 0° C. for a further 30 minutes. The reaction mixture is admixed with 300 ml of water and extracted with ethyl acetate (2×250 ml). The combined organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is used further as the crude product Rf=0.30 (EtOAc); Rt=4.33