Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([OH:9])[C:6]([OH:8])=O)[CH3:3].C(N(CC)C(C)C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:28][CH2:29][NH2:30])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:28][CH2:29][NH:30][C:6](=[O:8])[C@@H:5]([OH:9])[CH2:4][CH:2]([CH3:1])[CH3:3])=[CH:22][CH:21]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](O)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
L-2-hydroxyisocaproic acid (102 mg, 0.77 mmol) was dissolved in DMF (5 mL) and treated with N,N-diisopropylethylamine (0.53 mL, 3.06 mmol), 4,4-bis-(4-fluorophenyl)-butylamine (200 mg, 0.77 mmol), and HBTU (292 mg, 0.77 mmol), then stirred overnight at room temperature. The reaction was diluted with EtOAc (125 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed twice on silica gel, eluting with 2-4% MeOH/CH2Cl2 to give 139 mg (48%) of the desired product as an oil. MS: 376.2 (M+1 for C22H27N1O2F2); an oil; TLC (SiO2), Rf 0.73 (8% MeOH/CH2Cl2); HPLC (7:3 CH3CN/H2O with 0.1% TFA, C-18 column) 96.46%, RT=5.448 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][OH:33])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[CH3:34]I.[H-].[Na+]>CN(C=O)C.FC1C=CC=CC=1COC1C=CC([C@@H]2N(C(OC(C)(C)C)=O)[C@](CO)(C(OC)=O)CC2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][O:33][CH3:34])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: COC(=O)[C@]1(CO)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@@]1(C(=O)OC)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 109.7 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate (D66, 480 mg, 1.04 mmol) and methyl iodide (130 μl, 2 mmol) in dry DMF (5 ml) at 0° C. was added sodium hydride (60 mg, 1.5 mmol, 60% dispersion in mineral oil) and the mixture was stirred for 1.5 h from 0° C. to r.t. A second batch of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate (D62, 46 mg, 0.1 mmol) was dissolved in dry DMF (0.5 ml) and methyl iodide was added. The mixture was cooled at 0° C. and sodium hydride (6 mg, 0.15 mmol, 60% dispersion in mineral oil) was added and the mixture was stirred for 1.5 h from 0° C. to r.t. The reactions were quenched with brine/ice and the two mixtures were combined and extracted with ethyl acetate. The organic layer was washed three times with ice cold brine, dried (Na2SO4) and evaporated to afford the title compound as a colourless oil (540 mg); Rt (HPLC): 6.89 min; MS: (ES/+) m/z: 496 [M+Na] C26H32FNO6 requires 473; 1H NMR (400 MHz, CDCl3) δ(ppm): 7.48-7.59 (m, 1H); 7.42-7.48 (m, 2H); 7.28-7.36 (m, 1H); 7.13-7.21 (m, 1H); 7.03-7.13 (m, 1H); 6.89-7.00 (m, 2H); 5.13 and 5.16 (s, s, 2H); 4.94-5.06 and 4.74-4.83 (m, m, 1H); 4.09-4.19 (m, 1H); 3.78-3.96 (m, 1H); 3.83 (s, 3H); 3.41 (s, 3H); 2.44-2.70 (m, 1H); 2.17-2.36 (m, 2H); 1.69-1.87 (m, 1H); 1.11 and 1.40 (s, s, 9H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C@:17]4([CH3:23])[C:20]([CH3:22])([CH3:21])[C@H:13]3[CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:16]=34)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:31][Mg]I>O1CCCC1>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:19][CH2:18][C@:17]4([CH3:23])[C:20]([CH3:22])([CH3:21])[C@H:13]3[CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])([CH3:31])[CH3:29])=[CH:24][C:16]=34)=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: CC(=O)c1ccc2c(c1)[C@]1(C)CCN(C(=O)c3ccc4nc[nH]c4c3)[C@H](C2)C1(C)C
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)[C@]1(C)CCN(C(=O)c3ccc4nc[nH]c4c3)[C@H](C2)C1(C)C
Temperature: 0 °C

Procedure:
A solution of 1-[(2R,6S)-3-(3H-benzoimidazole-5-carbonyl)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl]-ethanone (0.10 g) in tetrahydrofuran (1 mL) is added to a solution of MeMgI (3 mol/L in Et2O, 0.25 mL) in tetrahydrofuran (1 mL) chilled in an ice bath (ca. 0° C.). Then, the cooling bath is removed and the solution is stirred at room temperature. After 5 h of stirring, more MeMgI (3 mol/L in Et2O, 0.25 mL) is added and the solution is stirred at 50° C. for 4 h. After cooling in an ice bath, aqueous NH4Cl solution is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by HPLC on reversed phase (MeCN/H2O).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:18])[C:5](=[N:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:19]OC(OC)N(C)C>>[CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:19]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1ccccc1)C(=O)OC
Product: COC(=O)c1nn(-c2ccccc2)cc(OC)c1=O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of methyl 4-methoxy-3-oxo-2-(phenylhydrazono)butanoate (25.03 g) in dimethylformamide dimethylacetal (120 mL) was stirred at 90° C. for 1 hr. The mixture was allowed to cool to room temperature, and stirred for 1 hr. The precipitate was collected by filtration, washed successively with diethyl ether and hexane, and dried to give the title compound (24.7 g) as pale-yellow crystals.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])(=[O:4])[CH:2]=[CH2:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9]>ClC(Cl)C>[C:1]([NH:5][C:6](=[O:7])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N=C=O
Reactant: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: C=CC(=O)NC(=O)OC(C)(C)C

Procedure:
To a solution of acryloyl isocyanate (9.7 g; 100 mmol) in dichloroethane (20 g), a solution of t-butanol (7.4 g; 100 mmol) in dichloroethane (20 g) was dropwise added under ice-cooling in 5 minutes. The solvent was removed by evaporation under reduced pressure to give t-butyl N-acryloylcarbamate as crude crystals, which were recrystallized from chloroform to give colorless needles. M.P., 131°-132° C.
Reaction SMILES: C[Li].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1.Cl[Si](C)(C)[CH3:17].Cl>O1CCCC1>[OH:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](=[O:11])[CH3:17])=[CH:6][CH:5]=1
Reactant: O=C(O)COc1ccc(O)cc1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)COc1ccc(O)cc1
Temperature: 22 °C
Reaction time: 40 h

Procedure:
Methyllithium (140 ml of 1.5 molar lithium bromide complex in diethyl ether) was added to a stirred solution of 4-hydroxyphenoxyacetic acid (7.6 g) in anhydrous tetrahydrofuran (500 ml) at 0°-10° C. under argon. The reaction mixture was stirred for 40 hours at 22° C., cooled in an ice-bath and chlorotrimethylsilane (39 ml) was added over 15 minutes. The temperature was allowed to rise to 22° C. and the reaction mixture was poured into 1N hydrochloric acid (360 ml) and stirred for 30 minutes. The product was extracted into ethyl acetate (4×200 ml) and the combined extracts washed with aqueous sodium bicarbonate (2×300 ml), brine (100 ml), dried and the solvent removed under reduced pressure. The crude ketone was purified by chromatography using 31/2% tetrahydrofuran in dichloromethane as eluent. The appropriate fractions were combined and evaporated to yield 1-(4-hydroxyphenoxy)propan-2-one (2.0 g) as a white solid, m.p. 110°-112° C. (from ethyl acetate); microanalysis: found C, 65.5; H, 6.1%; required for C9H10O3 : C, 65.1; H, 6.0%. (A similar procedure for the preparation of methyl ketones is described by G. M. Rubottom and Chong-Wan Kim, J.O.C. 1983, 48, 1550-1552).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)=[C:7]([N+:20]([O-])=O)[CH:6]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)=[C:7]([NH2:20])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cccc(CO)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(Nc2cccc(CO)c2)c(N)c1
Yield: 99 %

Procedure:
A solution of compound 5 (10 g, 30 mmol) in dry methanol (80 mL) was hydrogenated using Pd—C (1.0 g) as the catalyst (reaction monitored by TLC). The reaction mixture was filtered through celite. The filter cake was washed with methanol and the combined filtrate and washings were concentrated under reduced pressure to afford compound 6 (8.5 g, 93%) as a solid, which was taken as such for the next step.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:60]1([NH2:67])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:67][CH:60]3[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: NC1CCCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NC2CCCCCC2)cc1Cl
Reaction time: 8 h
Yield: 38.6 %

Procedure:
In THF (30 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(3-chloro-4-methoxybenzylamino)-pyrimidine-5-carboxylic acid (202 mg, 0.54 mmol) and DIEA (0.3 mL, 1.78 mmol). The reaction mixture was cooled in an ice bath, then HATU (250 mg, 0.65 mmol) and cycloheptanyl amine (67 mg, 0.60 mmol) were added. The react ion was conducted at ambient temperature overnight. The reaction mixture was concentrated, quenched with water and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=3/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-meth oxybenzyl)amino)-N-cycloheptanylpyrimidine-5-formamide (98 mg, 38.6% yield).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([OH:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[NH2:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[C:31](Cl)[CH:30]=[CH:29][N:28]=1>C1COCC1>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([O:23][C:31]2[CH:30]=[CH:29][N:28]=[C:27]([NH2:26])[C:32]=2[N+:33]([O-:35])=[O:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanol (0.782 g, 0.00217 mol) in THF (30.0 mL) was added NaH (0.156 g, 0.00650 mol) and the mixture was stirred for 1 h. To this was added 2-amino-4-chloro-3-nitropyridine (0.376 g, 0.00217 mol) and the mixture was stirred overnight. The solution was concentrated and the residue was purified by flash chromatography (25% EtOAc/hexanes) to afford the title compound (0.381 g, 35%) as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23](Cl)[CH:22]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:12][CH:10]2[CH2:11][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:22][CH:23]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Yield: 92 %

Procedure:
This material was prepared from 1-diphenylmethyl-3-azetidinol (6.0 g) and alpha,3,4-trichlorotoluene using the procedure described for compound (1) (yield 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]=[CH:12][N:13]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[OH:9])=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:11]=[CH:12][N:13]([C:15]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Mn+4]
Agent: [O-2]
Product: O=C(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 78 %

Procedure:
By the reaction in the same manner as in Example 24-(iii) using (4-bromophenyl)(1-trityl-1H-imidazol-4-yl)methanol (30.0 g) and manganese dioxide (52.6 g), the title compound (23.3 g) was obtained as colorless powder crystals.
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[S:11].CCOCC>CN(C=O)C>[CH3:8][N:9]([CH3:13])[C:10]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[S:11]
Reactant: Oc1cccnc1
Reactant: CN(C)C(=S)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C(=S)c1cccnc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a solution in DMF (50 mL) of 3-hydroxypyridine (4.76 g, 50 mmol) was added 1,1-diazabicyclo[2.2.2]octane (6.80 g, 150 mmol) and dimethylthiocarbamoyl chloride (18.5 g, 150 mmol) and the reaction mixture was stirred for 0.5 hours at ambient temperature and 18 hours at 55° C. The reaction mixture was cooled to ambient temperature and poured into ether. The ethereal solution was washed with aqueous 2N sodium hydroxide (2×), water (2×) and brine, dried, filtered and concentrated in vacuo. Chromatography on silica gel (1:1 ethyl acetate-hexane) gave 3-dimethylthiocarbamoylpyridine (5.46 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]12B[CH:27]([CH2:28][CH2:29][CH2:30]1)[CH2:26]CC2.IC1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: B1C2CCCC1CCC2
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Ic1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (4.9 g, 16.63 mmol) and 9-borabicyclo[3.3.1]nonane (199.6 ml, 99.78 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hours, add iodo-benzene (5.1 g, 24.95 mmol), triphenylphosphine (697.9 mg, 2.66 mmol), tetrakis(triphenylphosphine) palladium(0)(384.3 mg, 0.33 mmol), and 3N NaOH (13.7 mL) and stir at 60° C. After 22 hours, dilute the mixture with ethyl acetate and wash it with 1N sulfuric acid. Adjust the pH to 14, extract with ethyl acetate, and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using a ethyl acetate/hexanes gradient (5:95 to 10:90) to give (5.15 g, 84%) of the title compound as a white solid: mp 86–90° C.; mass spectrum (ion spray): m/z=371.3 (M+1).
Reaction SMILES: [CH2:1]([C:4]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:35]CC1>C1COCC1>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:7]2[CH2:6][CH2:5][C:4]([CH2:1][CH2:2][CH2:3][OH:35])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:9][C:8]2=[O:10])[CH:12]=1
Reactant: C=CCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Reactant: C1CCOC1
Agent: B
Product: O=C1OC(CCCO)(c2ccccc2)CCN1c1cccc(-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (18 mg, 0.045 mmol) in THF (1 mL) was added BH3.THF (60 μL, 1M THF solution) and the mixture was stirred overnight at rt. The reaction was cooled to 0° C. and NaBO3.H2O (19 mg, 0.20 mmol) was added and stirred for 2 h warming to rt. The solvent was removed in vacuo and the residue was redissolved in CH3CN (4 mL). The solution was filtered and purified by prep HPLC to afford 3-(2′,4′-difluorobiphenyl-3-yl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (4.44 mg). LC-MS Method 1, tR=1.97 min, m/z=424 (M+H). 1H NMR (CDCl3) 7.47-7.33 (m), 7.32-7.26 (m), 7.16-7.12 (m), 6.96-6.85 (m), 4.28 (t), 3.52-3.13 (m), 3.36-3.27 (m), 2.5-2.47 (m), 2.15-1.99 (m).
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH:11]([CH3:14])[CH2:12][OH:13])(=[O:9])[O:4]CCCC)[CH3:2].O>C(O)CCC.O>[CH2:1]([P:3]([CH2:10][CH:11]([CH3:14])[CH2:12][OH:13])(=[O:4])[OH:9])[CH3:2]
Reactant: CCCCOP(=O)(CC)CC(C)CO
Solvent: CCCCO
Solvent: O
Product: CCP(=O)(O)CC(C)CO
Reaction time: 4 h
Yield: 99 %

Procedure:
444 g (2 mol) of butyl ethyl(2-methyl-3-hydroxypropyl)phosphinate (produced as in Example 13) are initially charged to a 1 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. At 160° C., during 4 h, 500 ml of water are metered in and a butanol-water mixture is distilled off. The solid residue is recrystallized from acetone to obtain 329 g (99% of theory) of ethyl(2-methyl-3-hydroxypropyl)phosphinic acid as oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I.[OH:28][C:29]1[CH:39]=[CH:38][C:32]2[C:33](=[O:37])[CH2:34][CH2:35][O:36][C:31]=2[C:30]=1[CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:28][C:29]1[CH:39]=[CH:38][C:32]2[C:33](=[O:37])[CH2:34][CH2:35][O:36][C:31]=2[C:30]=1[CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C1CCOc2c1ccc(O)c2CCCc1ccccc1
Reactant: COC(=O)CCCOc1cccc(CCCCCCI)c1CCC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)CCCOc1cccc(CCCCCCOc2ccc3c(c2CCCc2ccccc2)OCCC3=O)c1CCC(=O)OC
Yield: 102.4 %

Procedure:
A mixture of 12.25 g (25 mmol) of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (preceding example), 7.1 g (25.2 mmol) of 2,3-dihydro-7-hydroxy-8-(3-phenylpropyl)-4H-1-benzopyran-4-one (example 9), 8.3 g (60 mmol) of anhydrous potassium carbonate, and 60 mL of dry acetonitrile was stirred and refluxed for 22 hr. After being cooled, the mixture was diluted with ether and filtered with suction. The solids were washed well with ether. The filtrate and washes were combined and concentrated in vacuo giving 16.5 g of a yellow oil. This material was chromatographed on silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 13.75 g (85.4%) of pure title dimethyl ester, as an oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C@@H:12]([OH:16])[C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(=O)Cc1ccc2c(c1)OCCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](O)Cc1ccc2c(c1)OCCO2
Temperature: -35 °C
Reaction time: 4 h

Procedure:
A solution of 12.4 g (23.0 mmol) (1R)—B-chlorodiisopinocampheylborane in 50 mL THF was added dropwise within 30 min to a solution of 4.6 g (20.7 mmol) 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-oxo-propionic acid and 3.14 mL (23.0 mmol) triethylamine in 150 mL THF cooled to −35° C. and the reaction mixture was kept for 1 h at this temperature and for 4 h at RT. To complete the reaction a solution of 5.0 g (9.3 mmol) (1R)—B-chlorodiisopinocampheylborane in 50 mL THF was added and the reaction mixture was stirred overnight at RT. THF was removed i.vac. and the crude product (2.0 g) was reacted further without purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:13][O:10][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: CO
Solvent: O
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 1771.5 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (5 g, 31.8 mmol) in dry MeOH (60 ml) was added freshly crystallized p-toluenesulphonic acid monohydrate (300 mg, 1.6 mmol). The reaction mixture was heated at 65° C. for 16 hrs. MeOH was removed in vacuo. The residue was taken up with saturated aqueous NaHCO3 solution (15 ml) and extracted with EtOAc. The combined organic layers were washed with water, and then with brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified by column chromatography over silica gel using 30% EtOAc/hexane) to provide the title compound as white solid (4.85 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:17])[NH:14][CH:13]([CH2:15][NH2:16])[CH2:12][O:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:18]OC(OC)N(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:17])[CH2:10][O:11][CH2:12][CH:13]3[CH2:15][N:16]=[CH:18][N:14]23)=[CH:7][CH:8]=1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C2(C)COCC(CN)N2)cc1
Solvent: ClCCl
Product: COc1ccc(C2(C)COCC3CN=CN32)cc1
Temperature: 25 °C

Procedure:
A solution of 31 mmol of C—[5-(4-methoxyphenyl)-5-methylmorpholin-3-yl]methylamine and 31 mmol of N,N-dimethylformamide dimethyl acetal in 50 ml of dichloromethane is heated to reflux for 6 hours. The reaction mixture is cooled to room temperature and evaporated. The crude title compound is obtained as a yellow oil from the residue and is employed without further purification in the next stage. Rf=0.17 (dichloromethane-methanol-25% aqueous ammonia solution 200:20:1), Rt=2.61 (gradient I)