Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].N1CCCC1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: C1CCNC1
Product: O=C(CN1CCOCC1)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure described in example 113, replacing 2-bromo-1-(3-bromophenyl)ethanone with 2-bromo-1-(4-bromophenyl)ethanone and pyrrolidine with morpholine. MS (ES) m/e 284 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:16]2[C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=[CH:12][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(=O)c1ccc(Oc2ccncc2[N+](=O)[O-])cc1

Procedure:
Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)-5-aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method C1a to afford the urea.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH:6]1[CH2:9][CH2:8][C:7]1=O.[NH2:17][CH2:18][CH2:19][OH:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][C@H:6]1[CH2:9][CH2:8][C@H:7]1[NH:17][CH2:18][CH2:19][OH:20]
Reactant: NCCO
Reactant: O=C1CCC1Oc1ccccc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: OCCN[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of C4 (3.5 g, 15 mmol) and 2-aminoethanol (1.03 g, 16.8 mmol) in 1,2-dichloroethane (100 mL) was treated with sodium triacetoxyborohydride (5.62 g, 25.2 mmol) and stirred at room temperature for 2 hours. The reaction was treated with acetic acid (4 mL) and stirred at room temperature for 16 hours. Aqueous sodium hydroxide solution (1 N, 100 mL) was added and the mixture was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 70% [10% 2 N ammonia in methanol/90% ethyl acetate] in ethyl acetate) afforded the title compound as a light amber oil. Yield: 2.1 g, 7.6 mmol, 51%. The indicated cis stereochemistry was tentatively assigned, based on NOE (nuclear Overhauser enhancement) experiments. 1H NMR (400 MHz, CDCl3) δ 7.57 (br dd, J=7.7, 1.3 Hz, 1H), 7.41-7.47 (m, 1H), 6.99 (br dd, J=7.6, 7.6 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 4.88-4.93 (m, 1H), 3.54-3.66 (m, 3H), 2.81-2.88 (m, 1H), 2.63-2.70 (m, 1H), 2.22-2.31 (m, 1H), 1.97-2.16 (m, 2H), 1.86-1.94 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[CH3:1][C:2]1[C:7]([N:8]=[C:15]=[S:16])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCOCC2)c1N
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(N2CCOCC2)c1N=C=S

Procedure:
Reaction of 6-methyl-2-morpholinoaniline (9.6 g) in dioxan (25 ml) and water (100 ml) with thiophosgene (5.7 ml) at 0° C. for 30 minutes and at room temperature for 3 hours gave 6-methyl-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.O.[NH2:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[NH2:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Nc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(-c2ccnc(N)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 100 ml flask was added 4-bromopyridin-2-amine 36.A (432 mg, 2.50 mmol, available from Apollo), 3-aminophenylboronic acid hydrate 36.B (465 mg, 3.00 mmol, available from Oakwood), tetrakis(triphenylphosphine)palladium(0) (288 mg, 0.25 mmol), DMF (5 mL) and saturated aqueous K2CO3 (5 mL). The reaction mixture was stirred at 80° C. overnight. The reaction was then extracted with DCM (2×50 mL), the organic layers combined, washed with brine and dried on MgSO4. The DCM was removed under vacuum, leaving a crude solution of 4-(3-aminophenyl)pyridin-2-amine in DMF to which was added more DMF (10 mL), (S)-2-(tert-butoxycarbonyl)-3-phenylpropanoic acid (662 mg, 2.5 mmol, available from Aldrich), diisopropylethylamine (1.74 mL, 10 mmol) and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate (1.90 g, 5.0 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then partitioned between water (50 mL) and EtOAc (100 mL). The layers were separated, and the aqueous phase was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography to afford tert-butyl (S)-1-(3-(2-aminopyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 36.C (200 mg, 15% yield).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][O:60][CH:61]1[CH2:64][N:63]([CH2:65][C:66]2[CH:71]=[CH:70][C:69]([CH2:72][NH:73][CH3:74])=[CH:68][CH:67]=2)[CH2:62]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:73]([CH2:72][C:69]3[CH:68]=[CH:67][C:66]([CH2:65][N:63]4[CH2:64][CH:61]([O:60][CH3:59])[CH2:62]4)=[CH:71][CH:70]=3)[CH3:74])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CC(OC)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CC(OC)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (45 mg, 0.12 mmol), EDCI (32 mg, 0.168 mmol), HOBt (24 mg, 0.18 mmol), DIPEA (0.04 mL, 0.24 mmol), 1-{4-[(3-methoxyazetidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (37 mg, 0.14 mmol) and DCM (10 mL).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH3:21]>>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH:9]=1
Reactant: Cc1ccc(F)cc1CBr
Reactant: NC(=O)c1cc(Cl)cnc1N
Product: Br
Product: Cc1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N

Procedure:
According to the method of Example 172, 2-amino-5-chloronicotinamide was reacted with 2-(bromomethyl)-4-fluoro-1-methylbenzene to give the title compound.
Reaction SMILES: CC#N.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)#[N:5].Cl.[NH2:20][OH:21].C([O-])(O)=O.[Na+]>CO>[OH:21][NH:20][C:4](=[NH:5])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:13])(=[O:14])[NH:15][CH2:16][CH2:17][OH:18])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(S(=O)(=O)NCCO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: N=C(NO)c1ccc(S(=O)(=O)NCCO)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 49.9 %

Procedure:
To a solution of 4-cyano-benzenesulfonyl chloride (1.00 g, 4.96 mmol) in THF, ethanolamine (454 mg, 7.44 mmol) is added. The mixture becomes slightly warm (30° C.) and turbid. The mixture is stirred at rt for 3 h before it is diluted with EA, washed with sat. aq. NH4Cl solution and water, dried over MgSO4, filtered and concentrated to give crude 4-cyano-N-(2-hydroxy-ethyl)-benzenesulfonamide (1.26 g) as a white solid; LC-MS: tR=0.34 min, [M+1+CH3CN]+=268.13. b) A mixture of 4-cyano-N-(2-hydroxy-ethyl)-benzenesulfonamide (1.25 g, 5.56 mmol), hydroxylamine hydrochloride (773 mg, 11.1 mmol) and NaHCO3 (934 mg, 11.1 mmol) in methanol is stirred at 60° C. for 7 h. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in EA (250 mL) and washed with water (5 mL). The organic extract is dried over MgSO4, filtered, concentrated and dried to give the title compound (720 mg) as a white solid; LC-MS: tR=0.23 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Si](Cl)(Cl)(Cl)Cl.[C:22](#N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(=O)([O-])[O-:32].[K+].[K+]>ClCCCl>[C:22]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH2:2][CH2:3]2)(=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1cccc2c1NCC2
Temperature: 160 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 357 mg (3 mmol) of indoline 3 dissolved in 10 ml of 1,2-dichloroethane are added 0.5 ml (3×1.2 mmol) of triethylamine, 0.44 ml (3×1.2 mmol) of boron trifluoride ether adduct, and 0.43 ml (3×1.2 mmol) of silicon tetrachloride, and the mixture is heated under reflux with stirring for 2 hours. The reaction mixture is evaporated; 0.62 ml (3×2 mmol) of benzonitrile is added to the residue and the mixture is heated at 160° C. with stirring for 5 hours and then cooled. The mixture is mixed with 5 ml of 6N hydrochloric acid and heated at 100° C. for 20 minutes. The reaction mixture is basified with potassium carbonate and extracted with dichloromethane. The organic layer is washed with water, dried over anhydrous potassium carbonate, and concentrated. The residue is chromatographed on a column of 4.6 g of silica-gel and eluted with dichloromethane. The eluate from dichloromethane is concentrated. The residue is recrystallized from ether-petroleum either to give 555 mg of 7-benzoylindoline 7 as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1C=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:12]=1C#N)[CH:6]=[CH:5]2.[OH-:23].[Na+].Cl.[CH2:26]([OH:29])[CH2:27]O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:27]=1[C:26]([OH:29])=[O:23])[CH:6]=[CH:5]2
Reactant: OCCO
Reactant: N#Cc1cc(C(F)(F)F)ccc1-n1ccc2cc(Cl)ccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(C(F)(F)F)ccc1-n1ccc2cc(Cl)ccc21
Temperature: 180 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzonitrile (1.66 g) and ethylene glycol (18 mL) was added a 1 M aqueous sodium hydroxide solution (26 mL) at room temperature, followed by stirring at 180° C. for 16 hours. The reaction mixture was cooled to room temperature and neutralized by adding 1 M hydrochloric acid (26 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(5-chloro-1H-indol-1-yl)-5-(trifluoromethyl)benzoic acid (1.67 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)=[CH:20][CH:19]=3)[CH3:17])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38]1([CH3:50])[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46](Cl)(=[O:48])=[O:47].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:50][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[C:39]=1[S:46]([N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:14][CH:13]=1)[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:22][CH:23]=1)[CH3:17])(=[O:47])=[O:48]
Reactant: CC(Nc1ccc(OCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)N(c2ccc(OCCN3CCCC3)cc2)C(C)c2ccc(OC3CCCCO3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
To a solution of [4-(2-pyrrolid in-1-yl-ethoxy)-phenyl]-{1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-ethyl}-amine (0.050 g, 0.12 mmol) in 0.4 mL methylene chloride was added triethylamine (0.05 mL, 0.36 mmol) and 2-mesitylenesulfonyl chloride (0.066 g, 0.30 mmol). The reaction mixture was stirred at room temperature for 3 days. PS-isocyanate resin (0.050 g) and PS-trisamine resin (0.050 g) were added and the reaction mixture was stirred at room temperature for 45 minutes. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to afford 0.071 g of the crude title compound of Step A which was used without further purification. MS 593.2 (M+1)+
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]([OH:10])[C:7]([OH:9])=O)[C:3]([OH:5])=O.[NH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[C:42]3[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=3)[CH2:36][N:35]([CH3:45])[CH2:34]2)[CH:28]=1)(=[O:26])=[O:25]>>[Cl:43][C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([Cl:44])[CH:39]=1)[CH2:36][N:35]([CH3:45])[CH2:34][CH:33]2[C:29]1[CH:28]=[C:27]([S:24]([NH:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][NH:11][C:3](=[O:5])[C@@H:2]([OH:1])[C@H:6]([OH:10])[C:7]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]3[C:42]4[C:37](=[C:38]([Cl:44])[CH:39]=[C:40]([Cl:43])[CH:41]=4)[CH2:36][N:35]([CH3:45])[CH2:34]3)[CH:28]=2)(=[O:26])=[O:25])=[O:9])(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)[C@@H](O)[C@H](O)C(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 32.1 %

Procedure:
Compound 222 was prepared following the procedure outlined in Example 215 using (2S,3S)-2,3-dihydroxysuccinic acid (15.5 mg, 0.103 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 112 mg, 0.206 mmol). Purification by preparative HPLC gave the title compound (39.9 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.87 (d, 2H), 7.77 (s, 2H), 7.63 (t, 2H), 7.54-7.50 (m, 4H), 6.82 (s, 2H), 4.34 (s, 2H), 3.90-3.85 (m, 1H), 3.62-3.30 (m, 47H), 3.14 (m, 8H), 3.05 (t, 4H). MS (m/z): 1206.95 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[C:23]([O:25]C2CCCCO2)[CH:22]=[CH:21][C:3]=1[C:4](=[O:20])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C2CCCCO2)=[CH:9][CH:8]=1.C(Cl)Cl.CO.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([C:3]2[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:2]=2[OH:1])=[O:20])=[CH:8][CH:9]=1
Reactant: O=C(C=Cc1ccc(OC2CCCCO2)cc1)c1ccc(OC2CCCCO2)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a mixture of 4,000 g of crude 2'-hydroxy-4,4'-bis(tetrahydropyranyloxy)chalcone (purity: 79.4%) and 13 ml of a mixed solvent of methylene chloride:methanol:water (4:4:1) was added 0.18 g of p-toluenesulfonic acid monohydrate, and the resulting mixture was agitated ar room temperature for 2 hours. The mixture was poured into 120 ml of water, and extracted with ethyl acetate. Distillation off of ethyl acetate afforded 2.770 g of 4,2',4'-trihydroxychalcone, having purity of 69.1% and yield of 99.9%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[CH:10]([CH3:13])[C:11]#[N:12].[C@@:21]12([CH2:31][S:32]([OH:35])(=[O:34])=[O:33])[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26][CH2:27]1)[CH2:24][C:22]2=[O:23]>CC(C)=O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C@@H:10]([CH3:13])[C:11]#[N:12].[C@@:21]12([CH2:31][S:32]([O-:35])(=[O:33])=[O:34])[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26][CH2:27]1)[CH2:24][C:22]2=[O:23]
Reactant: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Reactant: CC(C#N)C(O)(Cn1cncn1)c1cc(F)ccc1F
Solvent: CO
Solvent: CC(C)=O
Product: CC1(C)C2CC[C@]1(CS(=O)(=O)[O-])C(=O)C2
Product: C[C@@H](C#N)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile (2.7 g) in acetone (40 ml) a solution of (1R)-10-camphorsulfonic acid (2 g) in methanol (30 ml) was added and the mixture was heated under reflux until a solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the desired enantiomeric salt and let overnight. The solid was collected by filtration, washed with small amount of cold acetone and dried to provide (2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile-(1R)-10-camphorsulfonate as white solid. This salt was taken up in methylenechloride (20 ml) and water (ca. 30 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed with water (2×30 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (20 ml), heated for 10 min, cooled to 0° C. and stirred for ca. 2 hrs. The product was collected, washed with aqueous isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (1.05 g, 38% yield, 99% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[CH3:17][N:18]([CH3:25])[CH2:19][CH2:20][CH2:21]C(Cl)=O.[NH:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1>>[CH3:25][N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([N:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1)=[O:12])=[O:7]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CN(C)CCCC(=O)Cl
Reactant: OC1CNC1
Product: C=C1C[C@@H](C(=O)N2CC(O)C2)N(C(=O)CCCN(C)C)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, 4-(dimethylamino)butanoyl chloride, and 3-azetidinol the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=296.4.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[P:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15](=O)[CH2:14][C:13]2([CH3:22])[CH3:21])[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O)COCCO.O.NN.[OH-].[K+]>O.C(OCC)(=O)C>[CH3:21][C:13]1([CH3:22])[CH2:14][CH2:15][CH2:16][C:17]([CH3:18])([CH3:19])[P:12]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC1(C)CC(=O)CC(C)(C)P1c1ccccc1-n1cccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CCCC(C)(C)P1c1ccccc1-n1cccc1
Temperature: 210 °C
Reaction time: 7 h
Yield: 96.7 %

Procedure:
A round bottom flask was charged with 1-(2-(1H-pyrrol-1-yl)phenyl)-2,2,6,6-tetramethylphosphinan-4-one (878 mg, 2.80 mmol, 1.0 equiv) and purged with nitrogen for 15 minutes. Then nitrogen-sparged diethylene glycol (14.7 mL, 154 mmol, 55 equiv) was added and the flask was equipped with a Claisen adapter and a Dean-Stark trap. The flask was further charged with hydrazine hydrate (1.24 mL, 14.0 mmol, 5 equiv, 55 wt % hydrazine) and potassium hydroxide (786 mg, 14.0 mmol, 5 equiv), and the mixture was immersed in an oil bath at 60° C. The temperature of the bath was gradually increased to 210° C. over 1 hour and kept at that temperature for 7 hours. The reaction mixture was cooled to room temperature under a positive pressure of nitrogen and then diluted with water (50 mL) and ethyl acetate (20 mL). The phases were partitioned, and the organic layer was collected. The aqueous layer was washed with ethyl acetate (4×20 mL), and the combined organic fractions were washed once with aqueous saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated on a rotary evaporator to afford the title compound as a pale yellow solid (811 mg, 91 area % by HPLC, 97% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.96-7.83 (m, 1H), 7.35-7.22 (m, 2H), 7.22-7.17 (m, 1H), 6.72-6.66 (m, 2H), 6.20 (t, J=2.1 Hz, 2H), 1.87-1.71 (m, 2H), 1.71-1.56 (m, 2H), 1.50-1.33 (m, 2H), 1.11 (s, 3H), 1.06 (s, 3H), 0.76 (d, J=9.7 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 149.4-146.8 (m), 134.7 (d, J=4 Hz), 129.0, 127.8 (d, J=3 Hz), 126.5, 123.3 (d, J=3 Hz), 107.9, 37.6, 31.4, 31.1, 30.2 (d, J=7 Hz), 29.6 (d, J=18 Hz), 20.5. 31P NMR (CDCl3, 202 MHz) δ ppm −7.6 (s).
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH:11]=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.Cl([O-])=[O:14].[Na+].P([O-])(O)(O)=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[O:1]1[C:10]2[CH:9]=[C:8]([C:11]([OH:14])=[O:12])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1cc2c(cn1)OCCO2
Temperature: 25 °C
Reaction time: 19 h
Yield: 51.2 %

Procedure:
To a solution of 2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (722 mg, 4.37 mmol) in 2-methyl-2-propanol (95 mL) and 2-methyl-2-butene (22 mL) was added dropwise a solution of sodium chlorite (80%, 4.55 g, 40.22 mmol) and sodium dihydrogenphosphate (3.65 g, 26.45 mmol) in water (35 mL). The resulting solution was stirred at rt for 19 h. The volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and pH was adjusted to 3 by addition of 1N HCl. The aq. layer was extracted with DCM-MeOH 9-1 (25×30 mL). The combined extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated in ether and filtered to give the title acid as a white solid (0.405 g, 51% yield).