Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([S:10][CH2:11][CH2:12][CH3:13])[N:3]=1.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[NH2:24][C@H:25]1[C@@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@@H:28]2[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:2]([NH:24][C@H:25]2[C@@H:29]3[O:30][C:31]([CH3:33])([CH3:34])[O:32][C@@H:28]3[C@@H:27]([O:35][CH2:36][CH2:37][OH:38])[CH2:26]2)=[N:3][C:4]([S:10][CH2:11][CH2:12][CH3:13])=[N:5][C:6]=1[Cl:9]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Temperature: 95 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
A flask was charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (5 g), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (8.5 g), water (30 mL) and sodium bicarbonate (10.5 g). The mixture was heated to about 90-100° C. and maintained at the same temperature for about 8-9 hours and completion of the reaction was monitored by TLC. After completion of reaction the mixture was cooled to 25-30° C. followed by addition of water (100 mL) and toluene (50 mL). The mixture was stirred for about 20 minutes and layers were separated. The organic layer was washed with water (50 mL). The organic layer was separated and subjected to complete distillation under vacuum at 60-65° C. followed by cooling to room temperature and subsequent addition of n-heptane (75 mL). The mixture was stirred for about 2 hours followed by isolation of solid by filtration and washing with n-heptane (10 mL). The solid isolated was subjected to drying under vacuum at 60-65° C. for 1 hour to afford the title compound in about 80% yield having HPLC purity of about 99.03%.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[CH3:15][C@@H:16]1[O:21][C@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>C(O)CO>[CH3:22][CH:20]1[CH2:19][N:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[C:5](=[O:14])[NH:4][CH:3]=2)[CH2:17][CH:16]([CH3:15])[O:21]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)[nH]cc(N3CC(C)OC(C)C3)c2c1
Yield: 48.5 %

Procedure:
To a solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (0.2 g, 0.787 mmol) and (2S,6R)-2,6-dimethylmorpholine (0.181 g, 1.574 mmol) in ethylene glycol (2.5 ml) was added DIPEA (0.412 ml, 2.361 mmol). The reaction was irradiated in microwave at 145° C. for 1.5 h. The reaction mixture was adsorbed on silica was purified by silica gel chromatography (30% ethyl acetate in pet ether) to get desired compound (0.11 g, 48.5%) as solid. MS: MS m/z 289.18 (M++1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[NH:14]1[C:22]2[C:17](=[C:18]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.O1CCCC1>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:17]=3[CH:16]=[CH:15][NH:14]4)[CH2:24][CH2:25]2)=[O:13])=[CH:2]1
Reactant: O=C(O)Cc1coc2ccccc12
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cc1coc2ccccc12)N1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
A mixture of 2-(3-benzofuranyl)acetic acid (0.95 g), 1-(1H-indol-4-yl)piperazine (1.3 g), and N,N-dicyclohexylcarbodiimide (1.3 g) in a mixture of dry tetrahydrofuran (50 mL) and dry dimethylformamide (10 mL) was stirred for 16 h at room temperature. Filtration and removal of solvent in vacuo gave an oil which was purified by flash chromatography (eluent: ethyl acetate/heptane/triethylamine 10:9:1) giving 1-(3-benzofuranyl)methylcarbonyl-4-(1H-indol-4-yl)piperazine (0.5 g) as an oil. The oil was dissolved in tetrahydrofuran (20 mL) and treated with a suspension of lithium aluminium hydride (0.26 g) in tetrahydrofuran (20 mL) at room temperature under a nitrogen atmosphere followed by reflux for 4 hours. The reaction mixture was cooled to 0° C. and treated subsequently with water (1 mL), 15% aq. sodium hydroxide (0.5 mL), and water (2.5 mL). After stirring for 30 min the mixture was filtered and concentrated. The remaining oil was dissolved in acetone followed by addition of oxalic acid and filtration, giving the title compound as a crystalline material (0.4 g). Mp 130-32° C. 1H NMR (DMSO-d6): 3.05-3.15 (m, 2H); 3.15-3.30 (m, 6H); 3.35 (s, 4H); 6.45 (s, 1H); 6.55 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.20-7.40 (m, 3H); 7.60 (d, 1H); 7.75 (d, 1H); 7.90 (s, 1H); 11.10 (s, 1H). MS m/z (%): 346 (MH+, 3%), 214 (31%), 199 (19%), 171 (14%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[C:13]([C:14](=O)[CH3:15])=[C:12]([CH3:17])[N:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[C:10]=1[CH3:27])=O.[NH2:29][NH2:30]>C(O)C>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][C:7]1[C:9]2=[C:10]([CH3:27])[N:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=3)[C:12]([CH3:17])=[C:13]2[C:14]([CH3:15])=[N:30][N:29]=1
Reactant: NN
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(=O)CCCC(=O)OC)c2C)cc1
Solvent: CCO
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(CCCC(=O)OC)c3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]-5-oxo-pentanoic acid methyl ester (250 mg, 0.65 mmol) in ethanol (1 mL) was added a 1.0M solution of hydrazine in ethanol (0.72 mL, 0.72 mmol). The solution was stirred overnight at rt and concentrated in vacuo to give 4-[6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazin-1-yl]-butyric acid methyl ester as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.11-7.08 (m, 2H), 7.05-7.03 (in, 2H), 4.11 (q, 2H), 3.63 (s, 3H), 3.12 (t, 2H), 2.77 (s, 3H), 2.51 (t, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.14 (quintet, 2H), 1.47 (t, 3H); MS (ESI) 382 (M+H)+.
Reaction SMILES: [N:1]1([C:7](=O)[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1COCC1>[N:1]1([C:7](=[S:21])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#CCC(=O)N1CCOCC1
Solvent: C1CCOC1
Product: N#CCC(=S)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 131.2 %

Procedure:
To a solution of 3-morpholin-4-yl-3-oxopropanenitrile (3.0 g, 19.5 mmol) in anhydrous THF (45 mL) was added Lawesson's reagent (4.2 g, 10.3 mmol). The reaction mixture was allowed to stir at rt for 16 h and was then concentrated to small volume. A solid precipitated and was filtered. The solid was washed with diethyl ether to give 3-morpholin-4-yl-3-thioxopropanenitrile (2.3 g, 70%). LCMS: (AA) ES+ 171.2. 1H NMR (400 MHz, d1-chloroform) δ: 4.29-4.27 (m, 2H), 4.00 (s, 2H) and 3.83-3.81 (m, 6H).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[NH:20]2)=[CH:9]1)(C)(C)C.Br[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[O:28]=[S:21]1(=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:19]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[CH:9]=2)[N:20]1[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: BrCCc1ccccc1
Product: COc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1CCc1ccccc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 4, step c) and 2-bromoethylbenzene. 1H NMR (DMSO-d6) 13.03 (bs, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.65-7.60 (m, 2H), 7.50 (s, 1H), 7.29 (d, J=9.0 Hz, 1H), 7.25-7.13 (m, 4H), 7.09 (d, J=8.1 Hz, 2H), 6.74 (dd, J=2.4, 9.0 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 5.95 (s, 1H), 5.00 (s, 2H), 3.51 (s, 3H), 3.42 (ddd, J=6.3, 10.2, 15.9 Hz, 1H), 3.14 (ddd, J=5.7, 9.9, 15.0 Hz, 1H), 3.00-2.70 (m, 2H); MS: ESI (negative): 475 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[N+:31]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)([O-:33])=[O:32]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:40]([C:37]1[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:39][CH:38]=1)(=[O:41])=[O:42]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cc(Br)c2cc[nH]c2c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)c2ccn(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)c2c1
Temperature: 25 °C

Procedure:
4-Bromo-1H-indole-6-carbonitrile (207 mg), PS-BEMP (900 mg) and 4-nitrobenzenesulfonyl chloride (380 mg) were weighed to a round bottom flask, then N,N-Dimethylformamide (4 ml) was added and the reaction was stirred at RT. The reaction was filtered and washed with DMF. The DMF was evaporated and the residue was dissolved in DCM:methanol and passed through a 5 g SAX cartridge (preconditioned with methanol) washing with DCM:methanol. The residue was evaporated to afford the title compound, 360 mg as a pale orange solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.P(=O)(O)(O)O.[K].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: OB(O)C1CC1
Reactant: Brc1cncc2ccccc12
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(C3CC3)cncc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of 4-bromoisoquinoline (0.5 g, 2.403 mmol) and cyclopropylboronic acid (0.248 g, 2.88 mmol) in Toluene/water (11 ml, 10:1) was added phosphoric acid, potassium salt (1.02 g, 4.81 mmol) followed by addition of tricyclohexylphosphine (0.067 g, 0.240 mmol) and palladium(II) acetate (0.027 g, 0.120 mmol). The reaction mass was heated 100° C. and stirred for overnight. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.4 g, 93%) as an oil. 1H NMR (400 MHz, CDCl3): δ ppm 9.12(s, 1H), 8.34-8.32 (d, J=8 Hz, 1H), 8.31 (s, 1H), 7.98-7.96 (d, J=8 Hz, 1H), 7.76 (t, J=4 Hz, 1H), 7.62 (t, J=4 Hz, 1H), 2.23 (s, 1H), 1.11 (t, J=4 Hz, 2H), 0.82 (t, J=8 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].N1C=CC=CC=1>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
3-(4-Benzyloxyphenyl) propionic acid prepared in Example S (30 g, 117 mmol) was taken up in 300 mL of thionyl chloride. The reaction was kept under reflux for 5 hours, then cooled and concentrated. The residue was dissolved in 300 mL of CH2Cl2 and treated with N,O-dimethylhydroxylamine hydrochloride (14.1 g, 146 mmol) and 60 mL of pyridine at 0° C. The reaction was stirred overnight. The reaction was quenched with dilute HCl and extracted into EtOAc, and the organic layer was washed with sodium bicarbonate solution and dilute HCl and dried. The organic layer was dried (MgSO4) and concentrated. The residue was used further as crude reaction mixture or purified by flash silica gel column chromatography, eluting with EtOAc:hexane (1:9, then switching to 2:3).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:19]4[CH:18]=[CH:17][N:16]=[C:15]([O:20]C)[C:14]=4[C:13]([C:22]4[CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[S:25][CH:26]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C1COCC1.Cl>O>[O:20]=[C:15]1[C:14]2[C:13]([C:22]3[CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[S:25][CH:26]=3)=[N:12][N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[C:19]=2[CH:18]=[CH:17][NH:16]1
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(-c2nn(C3CCC(=O)CC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 4-(1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (20.0 mg) obtained in Step B of Example 148 in a mixed solvent of THF (5 mL) and water (0.50 mL) was added 6N hydrochloric acid (0.032 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (16.1 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:13]3[CH2:15][CH2:14]3)(O)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:31]3[C:30]4[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=4)[NH:33][CH:32]=3)([CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(O)(c1ccc2c(c1)OCO2)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCO4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.91 mmol) of the compound from Example 143A and 0.27 ml (3.49 mmol) of trifluoroacetic acid were added to 516 mg (2.91 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient). 377 mg (35% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:10]([O-:12])=[O:11])=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.S(Cl)(Cl)=O.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1[C:3]([C:10]([O:12][CH3:17])=[O:11])=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(C)c(C(=O)[O-])nc1C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1nc(C)c(C)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,5,6-trimethylpyrazine-2-carboxylate (5.38 g, 30.0 mmol) in methanol (90 mL) was added thionyl chloride (3.70 mL, 51.0 mmol) was added at 0° C. After being stirred at room temperature overnight, the reaction mixture was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo to give methyl 3,5,6-trimethylpyrazine-2-carboxylate. MS (APCI): m/z 181 (M+H).
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Si](C)(C)C)[CH:15]=[CH2:16].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:16]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:15]=[CH2:14]
Reactant: OC1(c2ccccc2)CCCCO1
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCC1(c2ccccc2)CCCCO1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-phenyltetrahydro-2H-pyran-2-ol (1.066 g, 5.98 mmol) and allyltrimethylsilane (1.901 mL, 11.96 mmol) in CH2Cl2 (25 mL) at 0° C. was added BF3.OEt2 (0.758 mL, 5.98 mmol) dropwise, and the mixture was stirred at the same temperature for 1 hr. Then the reaction was quenched with saturated NaHCO3 and the product was extracted with EtOAc. The extract was washed with brine, and the combined aqueous layers were back extracted with EtOAc once and combined. The extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (80 g silica gel) eluting with 1:9 followed by 4:6 EtOAc-hexane to give 2-allyl-2-phenyltetrahydro-2H-pyran as oil (0.954 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.10-7.45 (5 H, m), 5.47-5.65 (1 H, m, J=17.19, 10.11, 7.33, 7.33 Hz), 4.84-5.00 (2 H, m), 3.64-3.78 (1 H, m), 3.41-3.57 (1 H, m), 2.35-2.48 (1 H, m), 2.20-2.35 (1 H, m), 1.55-1.81 (4 H, m), 1.35-1.54 (2 H, m).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[F:9].CC(C)([O-])C.[K+].[CH2:37]([C@H:42]1[CH2:47][CH2:46][C@H:45]([CH:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)[CH2:44][CH2:43]1)[CH2:38][CH2:39][CH2:40][CH3:41].O>C1COCC1.C1(C)C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([CH2:10][CH:11]=[C:51]2[CH2:52][CH2:53][CH:48]([C@H:45]3[CH2:44][CH2:43][C@H:42]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:47][CH2:46]3)[CH2:49][CH2:50]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Reactant: CCCCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](C2CCC(=CCc3ccc(F)c(F)c3)CC2)CC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
43.01 g (89 mmol) of (3,4-difluorophenyl) ethyltriphenylphosphonium bromide were charged into a 300 ml three-necked flask in a nitrogen atomosphere and dried, and 74 ml of THF were added. The mixture was cooled to −30° C, a solution of 9.99 g (89 mmol) of potassium-t-butoxide in 70 ml of THF was added dropwise over a period of 15 minutes and the mixture was stirred for 1 hr. To this mixture was added dropwise a solution of 18.53 g (74 mmol) of 4-(trans-4-pentylcyclohexyl)cyclohexanone in 74 ml of THF over a period of 25 minutes. The mixture was stirred as such overnight and raised to room temperature. Water and toluene were added, the precipitate was filtered through Celite, and an organic layer and an aqueous layer were separated. The aqueous layer was extracted with toluene, an extract combined with the organic layer was washed with water, and dried over anhydrous magnesium sulfate. Triphenylphosphine oxide in the extract was filtered off, the solvent was distilled off and the solution was condensed. The concentrate was purified by column chromatography (elution solvent: heptane:ethyl acetate=20:1) to obtain 19.67 g of the eluate. Recrystallization at −30° C. from 50 ml of heptane-trace amount of solmix gave 14.31 g of the title compound (52%, Cr 38.4-38.5 Iso).
Reaction SMILES: [OH-].[K+].[C:3]([S:22][CH:23]1[NH:26][C:25](=[O:27])[CH2:24]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][N:26]1[CH:23]([S:22][C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:24][C:25]1=[O:27]
Reactant: COCCOCCl
Reactant: O=C1CC(SC(c2ccccc2)(c2ccccc2)c2ccccc2)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COCCOCN1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a suspension of tetrabutylammonium bromide (322 mg, 1 mmole) and potassium hydroxide (85%, 70 mg, 1.1 mmole) in dichloromethane (10 ml) cooled to 5° was added with vigorous stirring 4-tritylthio-2-azetidinone (345 mg, 1 mmole) and methoxyethoxymethyl chloride (187 mg, 1.5 mmole). The mixture was stirred at room temperature for 2 h, the solvent was evaporated and the residue partitioned between water and ethyl acetate. The dried organic phase was concentrated to leave a viscous oil (415 mg). Purification by column chromatography on silica gel eluting with ether (5%)-dichloromethane gave the title compound (206 mg, 48%) as an oil. δ (ppm, CDCl3): 7.30 (15H, m, aromatics), 4.57 (2H, AB quartet, N-CH2O), 4.46 (1H, dd, H-4), 3.50 (4H, s, OCH2CH2O), 3.30 (3H, s, CH3), 2.75 (2 H, m, H-3).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].[Cl-].[Mg+2].[Cl-].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](Cl)=[O:18].[Cl-].[NH4+]>O1CCCC1.[Cu]Br.O>[Cl:13][C:14]1[CH:15]=[C:16]([C:17](=[O:18])[CH2:2][CH2:3][CH:4]2[O:8][CH2:7][CH2:6][O:5]2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: BrCCC1OCCO1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCC1OCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (32.7 ml) was added dropwise within 15 minutes under argon and while stirring at a maximum 30° C. to a suspension of Rieke magnesium, prepared from 37.5 g of magnesium chloride, in 1200 ml of absolute tetrahydrofuran. The suspension was stirred at room temperature for 15 minutes, cooled to 0° C. and, after the addition of 36.4 g of copper(I) bromide, stirred at 0° C. for 15 minutes. After cooling to -70° C. 45.0 g of 3,4-dichlorobenzoyl chloride dissolved in 100 ml of absolute tetrahydrofuran were added dropwise within 20 minutes. The reaction mixture was stirred at -70° C. for 30 minutes and at room temperature for 2 hours and subsequently hydrolyzed with 800 ml of saturated ammonium chloride solution while cooling at a maximum 20° C. After the addition of 500 ml of water the mixture was extracted three times with ethyl acetate (1×800 ml, 2×500 ml). The combined organic extracts were dried over MgSO4 and freed from solvent. The residue, 65.0 g of brown oil, was chromatographed on 1500 g of silica gel with ethyl acetate/hexane (1:3) as the eluent. 30.4 g (51%) of 3',4'-dichloro-3-(1,3-dioxolan-2-yl)propiophenone were isolated as a yellow-orange oil.
Reaction SMILES: [NH2:1][CH:2]([P:6]([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>O>[C:12]([NH:1][CH:2]([P:6]([OH:8])[OH:7])[CH:3]([CH3:5])[CH3:4])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CC(C)C(N)P(O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(NC(=O)OCc1ccccc1)P(O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
27.5 parts of DL-1-amino-2-methylpropanephosphonous acid in 100 parts of water was stirred until solution occurred. The pH of the solution was adjusted to 9.5 with 4N sodium hydroxide and the mixture cooled to 0°. 34 Parts of benzyl chloroformate was added over 1 hour and the mixture stirred for 6 hours maintaining at pH 9.0-9.5 by periodic addition of 4N sodium hydroxide. The mixture was allowed to warm up to room temperature and then washed with ether. The aqueous portion was added slowly to a mixture of 120 parts of water and 80 parts of concentrated hydrochloric acid and 400 parts of ice. The solid which was obtained was dried and recrystallised from ethyl acetate/petroleum ether to give DL-1-carbobenzyloxyamino-2-methylpropanephosphonous acid, melting point 108°-111°.