Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1)#[CH:2].C([Li])CCC.[CH2:14]=[O:15]>>[C:3]1([C:1]#[C:2][CH2:14][OH:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1
Reactant: C=O
Reactant: C#CC1=CCCCC1
Agent: [Li]CCCC
Product: OCC#CC1=CCCCC1
Yield: 82 %

Procedure:
First, the appropriate alkynyl alcohols are synthesized. To produce the particular compositions disclosed herein, 1-Ethynylcyclohexene, for example, is deprotonated with butyl lithium and then condensed with paraformaldehyde (Brandsma and Verkruijsse). By this process, 3-Cyclohexenyl-2-propyn-1-ol was produced in 82% yield (Baudouy, et al.). This compound had been reported previously without complete spectroscopic data (Baudouy). 1-Ethynylcyclohexene (3.00 g, 28.6 mmol) was dissolved in diethyl ether (125 mL) and cooled to −78° C. 2.5 M n-butyllithium in hexane (12.4 mL, 31.1 mmol) was added dropwise. The solution was allowed to stir at −78° C. for 1.5 h and then paraformaldehyde (1.70 g, 56.5 mmol) was added. The reaction mixture was allowed to warm to 25° C. overnight. The mixture was poured into sat. NH4Cl solution (125 mL) and then extracted with diethyl ether (3×50 mL). The ether extracts were dried with MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using 1:1 diethyl ether/pentane to yield a light yellow oil (3.17g, 23.3 mmol, 82.4%). 1H NMR (CDCl3): 6.09 (m, 1 H), 4.35 (s, 2 H), 2.07 (m, 4 H), 1.62-1.57 (m, 5 H). EI HRMS (m/e) called for (M+)(C9H12O) 136.0888, found 136.0894.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=O)=[CH:26][CH:25]=1.O>C1COCC1>[CH3:22][N:23]([CH3:41])[C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:9][C:10]#[N:11])=[CH:26][CH:25]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=CC#N)c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (1.4 mL, 8.9 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 8.9 mL, 8.9 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of bis-(4-dimethylamino-phenyl)-methanone (1.19 g, 4.4 mmol) in THF (20 mL) and refluxed overnight. The reaction mixture was poured into water (20 mL), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give 3,3-bis-(4-dimethylamino-phenyl)-acrylonitrile as a light yellow needle-like solid (0.75 g, 58% yield): mp, 181-183° C.; 1H NMR (DMSO-d6) δ 2.96 and 2.98 (2s, 6H, 2N(CH3)2), 5.70 (s, 1H, CH), 6.67-6.80 (m, 4H, Ar), 7.15-7.23 (m, 4H, Ar); 13C NMR (DMSO-d6) δ 39.7, 39.8, 87.0, 111.3, 111.4, 120.0, 124.2, 125.6, 129.8, 130.7, 151.0, 151.5, 162.2. Anal. Calcd for C19H21N3: C, 78.32; H, 7.26; N, 14.42. Found: C, 78.33; H, 7.29; N, 14.38.
Reaction SMILES: [I:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH3:27]>CS(C)=O.O>[CH2:24]([N:7]1[C:6]2[CH:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:3]=[C:2]([I:1])[C:11]=2[O:10][CH2:9][C:8]1=[O:12])[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)c1cc(I)c2c(c1)NC(=O)CO2
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCN1C(=O)COc2c(I)cc(C(=O)OC)cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of Methyl 8-iodo-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (2.64 g) and potassium carbonate (5 g) in DMSO (20 mL) was added bromobutane (5 g), and the reaction mixture was stirred for 1 h at 80° C. The mixture was cooled to room temperature, diluted with 1:1 ethyl acetate/hexanes (100 mL) and water (160 mL), and separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:10 ethyl acetate/hexanes) afforded 2.24 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 8.13, 7.63, 4.74, 3.96, 3.92, 1.64, 1.42, 0.97.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (4.00 g; 17.4 mmol) is dissolved in methylene chloride (125 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (6.36 g; 20.9 mmol), diisopropylethylamine (7.27 g; 55.8 mmol), and PyBOP (10.89 g; 20.9 mmol) are added sequentially. The mixture is stirred for 14 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product as an oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)C(C)C)(C)C.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[N:41]=[C:42]=[O:43].Cl>C1(C)C=CC=CC=1>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[NH:41][C:42](=[O:43])[N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([CH3:22])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNCCc1ccc(CC(C)(C)C(=O)O)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCCCN(CCc1ccc(CC(C)(C)C(=O)O)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-[4-(2-heptylamino-ethyl)-phenyl]-2,2-dimethyl-propionic acid (23 mg, 0.072 mmol), and N,N-diisopropylethylamine (0.152 mmol, 0.0264 mL) dissolved in toluene (2 mL) was added 2,4-difluorophenylisocyanate (0.0796 mmol, 0.0094 mL). The mixture was allowed to stir at room temperature for 72 hours, then was poured over 1 M HCl (5 mL). The aqueous layer was isolated and extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), brine (2×), dried over anhydrous sodium sulfate, and concentrated to give a clear film. The crude product was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluting with 5% methanol/methylene chloride to give 3-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenyl)-2,2-dimethyl-propionic acid as a clear film (18.5 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]2([CH3:11])[CH2:10][O:9]2)=[CH:4][CH:3]=1.CC(C)=[O:16].S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([CH3:11])([OH:16])[CH2:10][OH:9])=[CH:4][CH:3]=1
Reactant: CC1(COc2ccc(Br)cc2)CO1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(O)(CO)COc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
2-[(4-Bromophenoxy)methyl]-2-methyloxirane (72.9 g, 300 mmol), acetone (360 ml), water (180 ml), and sulfuric acid (7.3 ml) were mixed and stirred at 60° C. for 1 hour. After cooling, the mixture was concentrated under reduced pressure. Ethyl acetate (360 ml) and a saturated sodium bicarbonate solution were added to the concentrated residue, followed by extraction. Thereafter, the ethyl acetate layer was dried over anhydrous sodium sulfate. Ethyl acetate (102 ml) was added to the resulting crude product and heated to dissolve the crude product. The resulting solution was cooled to room temperature, and then hexane (204 ml) was added thereto, followed by stirring at a temperature 10° C. or less for 1 hour. The precipitated crystals were collected by filtration and then washed with a mixture of ethyl acetate (24 ml) and hexane (48 ml). The resulting crystals were dried under reduced pressure, obtaining 44.0 g of the objective product (yield: 56%).
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[C:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(CCl)cs1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1csc(C(C)(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 20 h
Yield: 90.2 %

Procedure:
A mixture of 2-tert-butyl-4-chloromethyl-1,3-thiazole (8.66 g) and triethyl phosphite (15.7 g) was stirred at 160° C. for 20 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2 to 1:0, v/v) to give diethyl [(2-tert-butyl-1,3-thiazol-4-yl)methyl]phosphonate as a colorless oil (12.0 g, yield 90%).
Reaction SMILES: CC(C)([O-])C.[Li+].C(OP([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(OCC)=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1(/[CH:21]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a stirred mixture of lithium tert-butoxide (124.6 g, 1.56 mol, 1.10 equiv) in DCM (2000 mL) under N2 at RT was added ethyl 2-(diethoxyphosphoryl)acetate (317 g, 1.41 mol, 1.00 equiv). Benzaldehyde (150 g, 1.41 mol, 1.0 equiv) was then added dropwise to the stirred reaction, and the resulting reaction mixture was stirred under N2 at 25° C. overnight. The reaction mixture was diluted with DCM (2 L). The organic layer was washed with water (3×2 L) and brine (1×2 L), dried (Na2SO4), filtered, and evaporated in vacuo. The crude residue was purified by SiO2 chromatograph eluting with EtOAc/petroleum ether (3.3 to 1% EtOAc) to afford 180 g (72%) of ethyl (2E)-3-phenylprop-2-enoate (31) as a light yellow oil.
Reaction SMILES: Br[C:2]1([CH3:32])[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[CH:9]=[C:4]2[C:3]1=[O:31].CC(O)=O>CCOC(C)=O.[Zn]>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:7]1[N:6]=[C:5]2[O:24][C:25]3([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:2]([CH3:32])[C:3](=[O:31])[C:4]2=[CH:9][C:8]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: CC1(Br)C(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2OC12CCCCC2
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1C(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2OC12CCCCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product of Step B (20 mg, 0.037 mmol) was dissolved in EtOAc (1 mL) and AcOH (1 mL) and zinc (5 mg) were added. The reaction was stirred at rt for 10 min and concentrated. The residue was redissolved in CH2Cl2 and purified directly by silica gel flash chromatography gradient eluted with 0-15% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 452.4 (M+1), 545.4 (M+3); Rt=4.30 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12])[CH2:6][O:7][S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1cc(CO)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cc(COS(C)(=O)=O)cc(OC)c1OC
Yield: 51.6 %

Procedure:
To a stirred solution of 3,4-dimethoxy-5-propylbenzylalcohol (171 mg, 0.82 mmol) in CH2Cl2 (5.0 mL) at room temperature was added triethylamine (0.23 mL, 1.63 mmol) followed by methanesulfonyl chloride (95 μL, 1.22 mmol, 1.5 eq.). After 30 min the reaction mixture was diluted with hexanes (20 mL) and filtered through a pad of silica gel. The pad was then washed with 25% EtOAc in hexanes (100 mL). The combined organic filtrate was then concentrated to give methanesulfonic acid 3,4-dimethoxy-5-propylbenzyl ester (122 mg) as oil, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([NH:11][C:7]([CH:3]2[C:2]([CH3:10])([CH3:1])[C:4]2([CH3:6])[CH3:5])=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: CC1(C)C(C(=O)Nc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.7 %

Procedure:
A solution of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride (1.60 g, 10 mmole) in CH2Cl2 (5 ml) was added dropwise to a solution of aniline (2.8 g, 30 mmole) in CH2Cl2 (10 ml), while maintaining the temperature at 10°-20° C. The reaction mixture was stirred for 6 hours at room temperature, diluted with CH2Cl2 (15 ml) and washed successively with H2O (2×10 ml), 1N HCl (2×10 ml), H2O (20 ml) saturated NaCl (2×15 ml). The organic layer was separated, dried over MgSO4, and evaporated to dryness under reduced pressure. The residue was crystallized from EtOAc/hexane to afford 1.1 g (5.07 mmole, 51%) of a white crystalline solid), m.p. 149° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C@H:3]([CH3:22])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]2=[O:21])=[CH:7][CH:6]=1.Br[C:26]1[C:27](=[O:33])[N:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:32][N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([N:18]2[CH2:17][CH2:16][C:13]3([C:12](=[O:21])[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:22])[C:2]([F:1])([F:23])[F:24])=[CH:6][CH:7]=4)[CH2:15][CH2:14]3)[CH2:20][CH2:19]2)[C:27]1=[O:33]
Reactant: C[C@H](Oc1ccc(N2CCC3(CCNCC3)C2=O)cc1)C(F)(F)F
Reactant: Cn1cccc(Br)c1=O
Product: C[C@H](Oc1ccc(N2CCC3(CCN(c4cccn(C)c4=O)CC3)C2=O)cc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-[4-((S)-2,2,2-trifluoro-1-methylethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (prepared in analogy to example 1 step B-C from 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester and 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine) and 3-bromo-1-methyl-1H-pyridin-2-one. Light green solid. MS (ESI): 450.1 (MH+)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:15]=1[O:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][CH2:25][O:26][CH3:27])=[O:22])=[CH:19][CH:18]=1>>[Cl:34][C:32]1[CH:31]=[CH:30][C:15]([O:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][CH2:25][O:26][CH3:27])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:33]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Product: COCCNC(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 7d (111 mg, 0.62 mmol) was reacted with the product from Example 34e (200 mg, 0.62 mmol) for 18 h following the procedure from Example 7g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (89.4 mg, 25%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.73 (s, 3 H) 3.25 (s, 3 H) 3.32-3.50 (m, 4 H) 6.72 (d, J=6.99 Hz, 1 H) 6.97 (d, J=8.82 Hz, 2 H) 7.30 (d, J=8.82 Hz, 1 H) 7.61 (dd, J=8.82, 2.57 Hz, 1 H) 7.70-7.80 (m, 4 H) 8.42 (t, J=5.15 Hz, 1 H) 8.53 (d, J=6.99 Hz, 1 H) 8.82 (d, J=8.82 Hz, 1 H) 10.90 (s, 1 H) 14.54 (s, 1 H); MS (ESI+) m/z 463 (M+H−TFA)+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]1([P:11]([CH2:14]O)[CH2:12]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([P:11]([CH2:14][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:12][NH:4][CH:1]([CH3:3])[CH3:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: OCP(CO)c1ccccc1
Product: CC(C)NCP(CNC(C)C)c1ccccc1
Reaction time: 8 h

Procedure:
Degassed isopropyl amine (1 ml, 11.6 mmol) of was added to 491 mg (2.886 mmol) of (phenylphosphinediyl)dimethanol (PhP(CH2OH)2) and the mixture was stirred overnight. The excess amine was removed in vacuo to afford the product as a viscous colorless oil. 1H NMR (400 Mhz, C6D6): δ 7.55 (m, 2H); 7.09 (m, 3H); 3.11 (m, 4H); 2.68 (m, 2H); 0.89 (m, 12H). 31P NMR (162 Mhz, C6D6): −29.5.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:23]([Cl:24])=[CH:22][C:10]3[NH:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[O:31]1CCOCC1>O=[Mn]=O>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:23]([Cl:24])=[CH:22][C:10]3[NH:11][C:12]([C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=4)=[O:31])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: C1COCCO1
Reactant: Clc1cc2[nH]c(Cc3cccc(Br)c3)nc2cc1-c1ccc(-c2ccccc2)cc1
Agent: O=[Mn]=O
Product: O=C(c1cccc(Br)c1)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of compound 14-1 (270 mg, 0.57 mmol) in dioxane was added MnO2 (100 mg, 1.1 mmol). The reaction was allowed to stir at 70° C. for 48 h. The reaction mixture was filtered over a bed of Celite™ and washed with copious amounts of EtOAc. The product was concentrated in vacuo, and then purified on ISCO (EtOAc/Hexanes=1/1) to give the title compound 14-2 as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)#[N:2].[CH:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH2:13].Cl[O-].[Na+]>O1CCCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:13][CH:12]([CH2:14][C:15]([OH:17])=[O:16])[O:9][N:8]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=NO)cc1
Reactant: C=CCC(=O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2=NOC(CC(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a solution of 4-cyanobenzaldoxime (see Ex 43, Part A) (312 g, 2.13 mol) in tetrahydrofuran (3000 ml) at room temperature was added vinyl acetic acid (552 g, 6.41 mol). The yellow solution was cooled in an ice bath and sodium hypochlorite solution (5200 ml) was added in a dropwise fashion over 2h. After stirring overnight at room temperature the reaction was quenched with a 5% citric acid solution and diluted with 200 ml ether. The layers were separated and the aqueous acidified to pH 4 using citric acid. The acid layer was washed twice with 200 ml ether, the ether layers combined and extracted with saturated sodium bicarbonate solution. After acidifying the basic layer with citric acid, the product was extracted into 400 ml ether. The organic phase was washed three times with 150 ml water, once with brine, dried (MgSO4) and concentrated to give 220 g of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid as a white solid. Recrystallization from 25% water/ethanol yielded 165 g of analytically pure material. Anal. Calcd for C12H10N2O3 : C,62.61; H,4.38; N, 12.17. Found: C. 62.37; H 4.47; N, 11.71. 1H NMR(300 MHz, CDCl3): δ 7.77-7.76 (d, 2H, J=1.8 Hz); 7.72-7.71 (d, 2H, J=1.8 Hz); 5.22-5.14 (m, 1H); 3.63-3.54 (dd, 1H, J=10.6 Hz, 16.8 Hz); 3.19-3.11 (dd, 1H, J=7.3Hz, 16.8 Hz); 3.00-2.93 (dd, 1H, J=6.2 Hz, 16.5 Hz); 2.79-2.72 (dd, 1H, J=7.3 Hz, 16.5 Hz). IR(KBr pellet): 3202, 2244, 1736, 1610, 1432, 1416, 1194, 1152, 928, 840, 562 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C=[C:13]1C(OCC)=O>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH3:13])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: COc1ccc2cc[nH]c2c1
Product: COc1ccc2ccn(C)c2c1
Yield: 95 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting 6-methoxy-1H-indole for the ethyl indole-2-carboxylate, the title compound (2.3 g, 95%) was obtained as an oil: MS (ES) m/e 162.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)=[N:7]1)=[O:5])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCC(c2ccc(F)c(F)c2)=N1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(F)c(F)c2)N1
Reaction time: 16 h
Yield: 72 %

Procedure:
10% palladium on carbon (1.2 g, 50% water content) was added to an ethanol (160 mL) solution of (R)-5-(3,4 difluorophenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acid ethyl ester (12.2 g), and under a hydrogen atmosphere, stirring was continued for 16 hours at room temperature. The catalyst was filtered on celite, and the filtrate was concentrated, and ethanol (160 mL) and 10% palladium on carbon (1.2 g, 50% water content) was again added to the residue, and under a hydrogen atmosphere, stirring was continued for 15 hours at room temperature. The catalyst was filtered on celite, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate), and the title compound (8.86 g) was obtained. The physical property values are as follows.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C>O1CCCC1.O>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 55.4 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (282) (1.6 g. 3.48 mmol) in a mixture of tetrahydrofuran:water (2:1) (90 mL), was added lithium-hydroxide monohydrate (2.9 g, 69.57 mmol) and the reaction mixture was refluxed for 18 h. After completion of the reaction, all volatiles were evaporated, added water (30 mL) and washed with ethyl acetate (2×20 mL) to remove non acidic impurities. The separated aqueous part was acidified with 1N HCl to reach a pH of about 5 to 6. The acidified aqueous part was extracted with ethyl acetate (4×50 mL), dried and concentrated to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (780 mg, 55.44%) as a white solid.