Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:29][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[NH:20][CH:21]=[CH:22]3)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc3[nH]ccc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 96.5 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (110 mg, 0.330 mmol) was dissolved in dry DMF (0.5 mL) under nitrogen atmosphere. 1H-Indol-5-amine (131 mg, 0.991 mmol) was added and the reaction mixture was heated in a microwave reactor at 140° C. for 25 mins. The crude product was purified by preparative HPLC affording the title compound (126 mg, 96.5%). 1H NMR (500 MHz, CD3CN): δ 1.01 (t, 3H), 1.44-1.53 (m, 2H), 1.78-1.86 (m, 2H), 3.75 (t, 2H), 6.20-6.22 (m, 1H), 6.68-6.71 (m, 1H), 6.99-7.18 (m, 8H), 7.76 (bs, 1H), 9.18 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][N:12](CC2C=CC=CC=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[OH:10])=[CH:4][C:3]=1[Cl:35].Cl>C(O)C.[Pd]=O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[OH:10])=[CH:4][C:3]=1[Cl:35]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCc2ccccn2)Cc2ccccc2)cc1Cl
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccccn2)cc1Cl
Yield: 30.8 %

Procedure:
4-Amino-3,5-dichloro-α-[[(phenylmethyl)[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol (1.1 g) was hydrogenated over pre-reduced 10% palladium oxide on carbon (50% aqueous paste, 200 mg) in ethanol (10 ml) containing hydrochloric acid (conc. HCl/ethanol, 1:9 v/v, 4 ml). The catalyst was removed by filtration through hyflo, the solvent was evaporated and the residual oil was partitioned between 8% sodium bicarbonate (25 ml) and ethyl acetate (25 ml). The organic layer was washed with 8% sodium bicarbonate, water and brine, dried and concentrated to an orange oil which was purified by FCC eluting with System C (95:5:1→90:10:1) to give a yellow oil which was triturated with ether-hexane to give the title compound as a white solid (280 mg) m.p. 94°-96°.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=2[F:23])[N:8]=1)=[O:5].[P:29]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([O:31][CH2:32]Cl)=[O:30].[OH-].[K+]>CN(C)C=O>[P:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])([O:31][CH2:32][N:6]([C:4]([C:3]1[C:2]([F:1])=[CH:27][CH:26]=[CH:25][C:24]=1[F:28])=[O:5])[C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=2[F:23])[N:8]=1)=[O:30]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: O=C(Nc1ccn(Cc2c(F)cccc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(OCN(C(=O)c1c(F)cccc1F)c1ccn(Cc2c(F)cccc2C(F)(F)F)n1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A solution of 2,6-difluoro-N-(1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 29)(61.25 g, 153 mmol), chloromethyl bis(1,1-dimethylethyl) phosphate (for a preparation see Intermediate 60)(47.6 g, 184 mmol) and potassium hydroxide (14.18 g, 215 mmol) in N,N-dimethylformamide (500 ml) was stirred at ambient temperature for 7 days. The reaction mixture was partitioned between ethyl acetate (350 ml) and water/brine (250 ml, 1:1 volume/volume). The organic phase was washed with brine (250 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The sample was loaded in dichloromethane and purified on a silica Redisep cartridge 1500 g using a gradient of 0-75% ethyl acetate-cyclohexane over 8 column volumes. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless gum (which started to crystallise to a white solid (72.44 g); LCMS: (System 8) MH+=622, tRET=3.40 min.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:4]2[CH:5]=[CH:6][O:2][CH:3]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCC(=O)c1ccoc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccc(Cl)cc1)c1ccoc1
Yield: 100.5 %

Procedure:
5 g of (3-furylcarbonyl)methylamine hydrochloride, 6.0 g of sodium bicarbonate and 6.0 g of 4-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 8.2 g of N-(4-chlorobenzoyl)-(3-furylcarbonyl)methylamine are thereby obtained. Yield: 100%
Reaction SMILES: [I-].[Na+].C([BH3-])#N.[Na+].Cl[CH:8]([N:22]1[CH:25]([S:26][CH3:27])[CH2:24][C:23]1=[O:28])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:27][S:26][CH:25]1[N:22]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[C:23](=[O:28])[CH2:24]1
Reactant: CSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSC1CC(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
Sodium iodide (687 mg) and sodium cyanoborohydride (576 mg) were added to a solution of crude p-nitrobenzyl 2-chloro-2-(4-methylthio-2-azetidinon-1-yl)acetate (1.58 g) in hexamethylphosphoramide (15 ml), and the resulting mixture was stirred at room temperature for an hour. The reaction mixture was then poured into ice-water and the precipitates produced were collected by filtration, washed with water, dried and recrystallized from ethyl acetate to afford 844 mg of the desired compound.
Reaction SMILES: [OH:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[C:14](#[N:18])[CH2:15][C:16]#[N:17].C(NCC)C>C(O)C>[NH2:18][C:14]1[O:1][C:2]2[CH2:3][N:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=2[C:15]=1[C:16]#[N:17]
Reactant: CCOC(=O)N1CCC(=O)C(O)C1
Reactant: N#CCC#N
Solvent: CCNCC
Solvent: CCO
Product: CCOC(=O)N1CCc2c(oc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
Ethyl 3-hydroxy-4-oxopiperidine-1-carboxylate from Example 35A (4.00 g, 21.4 mmol) was dissolved in ethanol (10 mL), and propanedinitrile (1.41 g, 21.4 mmol) was added. Within 10 min, diethylamine (1.56 g, 21.4 mmol) was added dropwise, whilst the temperature was kept below 35° C. Subsequently, the reaction mixture was stirred for 20 h at rt. The precipitate was collected by suction filtration and washed with ethanol and diethyl ether to yield 2.00 g (39%) of the title compound.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.CC(C)([O-])C.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[O:71]1[C@H:73]([CH:74]([CH3:76])[CH3:75])[CH2:72]1.[Si](O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC=C2[C@@H](OC[C@H](O)C(C)C)C)C[C@@H](O[Si](C(C)(C)C)(C)C)C1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C1(C)C=CC=CC=1>[OH:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:72][C@H:73]([OH:71])[CH:74]([CH3:76])[CH3:75])[CH3:22])[CH2:12][C@@H:11]([OH:31])[CH2:10]1
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)[C@@H]1CO1
Agent: CC(C)(C)[O-]
Agent: CC(C)[C@@H](O)CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](O)CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 22.5 %

Procedure:
Using 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (71.5 mg, 0.128 mmol), potassium t-butoxide (170 mg, 1.52 mmol), dibenzo-18-crown-6 (32.0 mg, 0.0888 mmol), toluene (4.5 ml) and (R)-(−)-1,2-epoxy-3-methylbutane (0.13 ml, 1.24 mmol), alkylation reaction (108° C., 1 hour) and work up were performed by the same procedure as in Example 119, and then the residue was separated by preparative thin layer chromatography (0.5 mm×3, hexane:dichloromethane:ethyl acetate=45:5:2, developed three times) to give a fraction containing 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{2(R)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene (26.8 mg). This was deprotected with tetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.4 ml) (reaction temperature 74° C., reaction period 12 hours) and worked up by the same procedure as in Example 119, and then the residue was purified by preparative thin layer chromatography (0.25 mm×1, dichloromethane:ethanol=15:1, developed twice) to give the title compound as a colorless oil (12.0 mg, 23%).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:8](O)[CH3:9]>>[NH:4]1[CH2:2][CH2:9][CH2:8][CH2:7][CH2:5]1.[NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: CCO
Agent: O=C1CNC(=O)N1
Product: C1CCNCC1

Procedure:
The resulting aldehydes (22) could be reacted with hydantoin in ethanol with a base, such as, piperidine to give the desired pyrazolo[1,5-a]pyrimidin-3-ylmethylene)imidazolidine-2,4-dione of structure 23. Additionally, the corresponding thiazolidine-2,4-dione and the Rhodanine derivatives of compounds 23 could be synthesized using the aforementioned methods.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[N:17]=[C:16]([CH2:18][CH2:19][CH:20]4[NH:26][C:25](=O)[CH2:24][CH2:23][CH2:22][CH2:21]4)[NH:15][C:12]3=[N:13][CH:14]=2)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[N:17]=[C:16]([CH2:18][CH2:19][CH:20]4[NH:26][C:25](=[S:37])[CH2:24][CH2:23][CH2:22][CH2:21]4)[NH:15][C:12]3=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1
Product: COc1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Yield: 83 %

Procedure:
The title compound is synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 120 mg of 7-{2-[6-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-azepan-2-one (compound B3) and 222 mg of Lawesson's reagent. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 104 mg of the title compound as a light yellow, waxy solid. ESI-MS: 381.2 (MH+). TLC: Rf=0.64 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>>[Br:1][C:2]1[C:3]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:22])[F:23])[CH:16]=2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: COC(=O)c1cnc(Oc2cccc(C(F)(F)F)c2)c(Br)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from methyl 5-bromo-6-chloronicotinate and 3-(trifluoromethyl)phenol.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH:20]([CH3:26])[CH:21]=[CH:22][C:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br-].C([N+](CCCC)(CCCC)CC)CCC.Cl>O.ClC1C=CC=CC=1>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:20]([CH3:26])[CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(Br)C=CC(=O)[O-]
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CCCC[N+](CC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1
Solvent: O
Product: CC(C=CC(=O)O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 6 h
Yield: 91.2 %

Procedure:
In a reactor, 100 ml of chlorobenzene and 100 ml of water were charged and 95.3 g (0.375 mole) of 4-(4-trifluoromethylphenoxy)phenol, 73.7 g (0.412 mole) of 4-bromo-2-pentenoate, 78.0 g (0.56 mole) of potassium carbonate and 1.1 g (0.00375 mole) of tributylethylammonium bromide were added. The mixture was refluxed with stirring for 6 hours. The reaction mixture was cooled to the room temperature and conc. hydrochloric acid was added to the reaction mixture with stirring to be acidic. The water phase was separated and the organic phase was washed with water and chlorobenzene was distilled off at 100° C. under a reduced pressure of 0.02 to 0.05 mmHg to obtain 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoic acid. The yield was 91.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][CH:17]=[CH:18][CH:11]3[C:10]2=[O:19])=[CH:4][C:3]=1[OH:20].[N+:21]([O-])([OH:23])=[O:22]>>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:5]([N:9]2[C:10](=[O:19])[CH:11]3[CH2:18][CH2:17][CH:16]=[CH:15][CH:12]3[C:13]2=[O:14])=[C:6]([F:8])[CH:7]=1
Reactant: O=C1C2C=CCCC2C(=O)N1c1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])O
Product: O=C1C2C=CCCC2C(=O)N1c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2-Chloro-4-fluoro-5-(tetrahydrophthalimido)phenol (5.0 g) was added into nitric acid (50 ml) at 0° C., warmed up to room temperature in 30 minutes. Crushed ice was added and the solution extracted with methylene chloride. The organic phase was washed with water, dried over anhydrous sodium sulfate, and purified by a silica gel column, eluted with metliylene chloride-ethyl acetate (19:1) to give 3.67 g of the desired product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[CH:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O>C(O)C.[Pd]>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][CH2:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Agent: [Pd]
Solvent: CCO
Product: c1cncc(CCc2cccc(C[C@@H]3CNCCO3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Boc-(R)-2-(3-(2-(3-pyridinyl)vinyl)-benzyl)morpholine intermediate (a) was dissolved in ethanol (8 mL), with palladium on charcoal (10% w/w, 5 mg) and stirred at room temperature under an atmosphere of hydrogen (1 balloon containing hydrogen) for 18 hours. The reaction was filtered through a pad of celite, washing with ethanol, and the solution was concentrated in vacuo. The crude material was used in the next step without further purification. N-Boc-(R)-2-(3-(2-(3-pyridinyl)ethyl)-benzyl)morpholine (25 mg), was dissolved in a solution of TFA in dichloromethane (20% v/v, 1 mL total) and stirred at room temperature for 3 hrs. The reaction was then poured through an SCX-2 column and washed with dichloromethane. The column was then washed with ammonia (2N, methanol) and the ammonia washes concentrated in vacuo. The residue was purified by column chromatography (prepacked silica, 1 g; dichloromethane/methanol/ammonium hydroxide, 100:10:1) to obtain the desired product example 48 (R)-2-(3-(2-(3-pyridinyl)ethyl)benzyl)morpholine as a yellow oil (10 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2=[O:18].[Br-].[CH2:20]1COC[CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2([CH:20]=[CH2:21])[OH:18]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(Br)cc21
Reactant: C1CCOC1
Agent: [Br-]
Product: C=CC1(O)CC(c2ccccc2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-2-phenylchroman-4-one (2.021 g, 6.67 mmol) in anhydrous THF (35 mL) at −78° C. is added a solution of vinylmagnesiun bromide in THF (1 M, 10 mL, 10 mmol) dropwise within 30 min. The reaction temperature is allowed to warm to rt and stirred for another 2 h. The reaction is chilled to 0° C. and quenched with sat. aq. NH4Cl and extracted with ethyl acetate (2×40 mL). The combined organic phases are washed with H2O, brine, and dried over Na2SO4, and filtered. The filtrate is concentrated and the residue is purified through flash chromatography on silica gel to afford 6-bromo-2-phenyl-4-vinylchroman-4-ol as an oil (1.961 g. 89%). MS ESI+ve m/z 313 (M+H—H2O)+.
Reaction SMILES: [CH2:1]([Si:3]([CH2:12][CH3:13])([CH2:10][CH3:11])[C:4]#[C:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].[I-:14].[I-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C(#N)C>[CH2:1]([Si:3]([CH2:12][CH3:13])([CH2:10][CH3:11])[C:4]#[C:5][CH2:6][CH2:7][CH2:8][I:14])[CH3:2]
Reactant: CC[Si](C#CCCCO)(CC)CC
Reactant: [I-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC[Si](C#CCCCI)(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(triethylsilyl)-4-pentin-1-ol (416 g, 2.1 mmol) in absolute acetonitrile (20 mL was added in drops to a solution of triphenylphosphine diiodide (2.80 g, 5.4 mmol) and imidazole (1.04 g, 15.4 mmol) with argon and stirred overnight at room temperature. The raw product was purified by means of flash chromatography (38 g, 20×2.5 cm) with cyclohexane/ethyl acetate (9:1).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:11]=1[NH2:12].[CH:18]1([N:21]2[C:30]3[C:25](=[C:26](F)[C:27]([F:32])=[CH:28][C:29]=3[F:31])[C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22]2)[CH2:20][CH2:19]1>C1COCC1.CN1C(=O)CCC1>[CH:18]1([N:21]2[C:30]3[C:25](=[C:26]([NH:12][C:11]4[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:10]=4[F:9])[C:27]([F:32])=[CH:28][C:29]=3[F:31])[C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22]2)[CH2:19][CH2:20]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)cc(F)c(F)c2c1=O
Reactant: Nc1ccc(I)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=C(O)c1cn(C2CC2)c2c(F)cc(F)c(Nc3ccc(I)cc3F)c2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.3 %

Procedure:
LDA (2N solution in heptane/tetrahydrofuran/ethylbenzene, 0.39 mL, 0.77 mmol) was added dropwise to a stirred solution of 2-fluoro-4-iodoaniline (165 mg, 0.70 mmol) in THF (1.2 mL) at −78° C. After 15 minutes, a solution of example 1d (100 mg, 0.35 mmol) in NMP (1.8 mL) was then added at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 25 h. Purification by preparative HPLC mass triggered gave 7.6 mg (5%) of the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.92 (s, 1H), 10.39 (s, 1H), 8.71 (s, 1H), 8.11 (t, 1H, J=11.2 Hz), 7.65 (d, 1H, J=10.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 6.74-6.79 (m, 1H), 4.12-4.19 (m, 1H), 1.15-1.22 (m, 4H). MS (ES) [m+H] calc'd for C19H12F3IN2O3, 501; found 501.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[O:10]([C:17]1[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:10]([C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC1CN2CCC1CC2
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Oc2cccc(OC3CN4CCC3CC4)c2)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) in tetrahydrofuran (anhydrous, 10 mL) was treated with 3-phenoxyphenol (Aldrich, 186 mg, 1 mmol), DIAD (diisopropyl azadicarboxylate, Aldrich, 404 mg, 2 mmol), and triphenylphosphine (Aldrich, 522 mg, 2 mmol) at ambient temperature for two days. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.30) as oil (250 mg, yield, 85%). 1H NMR (MeOH-d4, 300 MHz) δ 1.42–1.58 (m, 1H), 1.64–1.75 (m, 1H), 1.78–1.88 (m, 1H), 2.00–2.15 (m, 1H), 2.16–2.24 (m, 1H), 2.80–3.1 3.34–3.40 (m, 1H), 4.52 (m, 1H), 6.52 (m, 2H), 6.67(dd, J=2.4, 1.0 Hz, 1H), 6 2H), 7.11 (tt, J=7.5, 1.7 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.35 (m, 2H) ppm. MS (DCl/NH3) m/z 296 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH:11]=O)[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].[CH:20]([NH2:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C=O
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(C)C
Reaction time: 4 h

Procedure:
A solution of (3S*,4S*)-4-formyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.87 g, 10.56 mmol) and isopropylamine (2.72 mL, 31.68 mmol) in 1,2-dichloroethane (150 mL) is stirred 25 min, before addition of NaBH(OAc)3 (3.12 g, 14.78 mmol) follows. The solution is stirred for 4 h, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The combined organic extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 80:20) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.1.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([P:30](=[O:33])([OH:32])[OH:31])[CH3:29])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:25]([NH:27][C@H:28]([P:30](=[O:31])([OH:33])[OH:32])[CH3:29])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CC(C)C[C@H](N)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that given in Example 1 (b), from the benzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-leucyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-leucylamino)-ethylphosphonic acid of melting point 238° -240° C (decomposition); [α]D20 = - 14.2° (c = 0.5% in water).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1)([CH3:3])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[K+].[OH-].[Na+]>OS(O)(=O)=O>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)C1=NCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: CC(C)C1=NCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 13F (0.73 g, 4.2 mmol) in concentrated H2SO4 (7.5 mL) at 0° C. was treated with KNO3 (0.47 g, 4.6 mmol), stirred for 30 minutes, treated with ice water, adjusted to pH>7 with 25% NaOH, and extracted with dichloromethane. The combined extracts were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetatehexanes to provide the desired product.