Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: c1ccoc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(CC(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
3-Methoxyphenylacetic acid (20 g, 120.35 mmol) was dissolved in CH2Cl2 (200 mL), and furan (24.6 g, 361.39 mmol) and trifluoroacetic anhydride (37.8 g, 180 mmol) were added to the solution. The reaction was kept being stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 to pH=6.9, and the organic reagent in the mixture was evaporated. The residue was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give 1-(furan-2-yl)-2-(3-methoxyphenyl)ethan-1-one as yellow oil: 20 g (yield: 77%)
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]=[O:5].C(N(CC)CC)C.[CH2:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[CH2:15][CH2:14]1.Cl>O1CCCC1>[OH:22][C:17]1[C:18]([CH:4]=[O:5])=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][CH2:13]2
Reactant: C=O
Reactant: Oc1cccc2c1CCC2
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1O)CCC2
Temperature: 72.5 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirred suspension Magnesium chloride (71.0 gm, 0.745 mole) and Para-formaldehyde (33.6 gm, 1.12 mole) in Tetrahydrofuran (200 ml), Triethylamine (104 ml, 0.745 mole) was added at room temperature and stirred for 30 minutes. To the reaction mixture; the solution of Indan-4-ol (50 gm, 0.373) in Tetrahydrofuran (100 ml) was added at room temperature and heated to 70-75° C. for 6 hours. To the reaction mixture, 2N Hydrochloric acid (600 ml) was added and extracted with Ethylacetate (2×500 ml). The Ethylacetate layer was washed with water (300 ml), dried over Sodium sulphate and further it was distilled under vacuum to give viscous oil (52.0 gm) which becomes solid upon keeping.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12>O1CCCC1>[C:44]1(=[O:54])[N:48]([CH2:23]/[CH:22]=[CH:21]\[CH2:20][O:19][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12
Reactant: OC/C=C\COC1CCCCO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C/C=C\COC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
Under a nitrogen atmosphere diethylazodicarboxylate (1.6 ml, 10 mmol) was added to a cooled (0° C.) solution of cis-4-tetrahydropyranyloxy-2-butene-1-ol (1.7 g, 10 mmol), triphenyl phosphine (2.2 g, 10 mmol) and phthalimide (1.47 g, 10 mmol) in anhydrous tetrahydrofuran (50 ml). When the addition was completed (5 min) the reaction mixture was allowed to warm at room temperature and was stirred 12 h. Then the mixture was concentrated in vacuo, diluted with ethyl acetate (200 ml) and washed with brine (150 ml). After usual work-up (the aqueous phase was extracted three times with 100 ml portions of ethyl acetate), the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo) the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 2:8) to give 1.9 g of the title compound (64%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.CC[O-].[Na+].[Na].[F:16][C:17]([F:24])([CH3:23])[C:18](OCC)=O>C(O)C>[F:16][C:17]([C:23]1[N:1]=[C:2]2[N:3]=[C:4]([CH3:10])[CH:5]=[C:6]([OH:9])[N:7]2[N:8]=1)([F:24])[CH3:18]
Reactant: CCOC(=O)C(C)(F)F
Reactant: Cc1cc(=O)n(N)c(N)n1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1cc(O)n2nc(C(C)(F)F)nc2n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Intermediate 1 was added to a stirring solution of NaOEt prepared from sodium (FLUKA, 3.28 g, 143 mmol) and ethanol (150 ml) and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled down to room temperature and ethyl 2,2-difluoropropanoate (FLUOROCHEM, 11.83 g, 86 mmol) was added. The mixture was stirred at room temperature for 30 min before being heated to 80° C. for 1.5 h. The reaction mixture was concentrated to dryness and water (200 mL) was added. The reaction mixture pH was adjusted to 4 by addition of 2N HCl solution while a white solid precipitated. The solid was filtered, washed with water and dried under vacuum to afford Intermediate 2. The mother liquors were extracted with DCM (5×35 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give more Intermediate 2 as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[Br:16]Br.C(N(CC)CC)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)(Cl)Cl>[Br:16][CH:8]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution tert-butyl 4-oxoazepane-1-carboxylate (compound 82.2, 11.0 g, 51.6 mmol) in chloroform (220 mL) at 0° C. was added drop-wise a solution of bromine (3.98 mL, 77.6 mmol) in chloroform (110 mL). The resulting mixture was stirred at room temperature overnight, then the solids that formed were collected by filtration and dissolved in dichloromethane (200 mL). Triethylamine (16.8 mL, 121 mmol) and (Boc)2O (8.70 g, 40.3 mmol) were added to the mixture at 0° C. and the resulting solution was stirred for 3 h at room temperature, and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:10) as the eluent to give 4.0 g (27%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[NH2:32][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)N(C)C)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)N(C)C)CC1
Temperature: 65 °C

Procedure:
A mixture of 4-(7-acetyl-5-chloroquinolin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (0.027 g, 0.075 mmol) and ammonium acetate (0.0576 g, 0.747 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.19 mL, 0.19 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C15H25ClN5O (M+H)+: m/z=362.2; Found: 362.2.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[CH2:10]=O>O.[Pd]>[CH3:10][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCNCC1
Reactant: C=O
Agent: [Pd]
Solvent: O
Product: CN1CCC(C(N)=O)CC1
Reaction time: 43 h
Yield: 64.5 %

Procedure:
Isonipecotamide (10 g, 78.0 mmoles) was dissolved in distilled water (100 mL) and 37% aqueous formaldehyde (7.6 mL, equivalent to 2.81 g HCHO, 93.6 mmoles) was added. Wet 10% Pd—C (8 spoon spatulas) was added under argon and the mixture was hydrogenated at 25° C. and 50 psi for 43 h. The catalyst was filtered off through Celite and the latter was washed with water and methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on a silica gel column (60×5 cm) using 8%-10%-20% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 1-methylisonipecotamide (7.15 g, 64%): FABMS: m/z 143.1 (MH+); HRFABMS: m/z 143.1184 (MH+). Calcd. for C7H15N2O: m/z 143.1184; δH (d6-DMSO) 1.50/1.57 (4H, m, CH2), 1.76/1.94 (4H, m, CH2), 2.10 (3H, s, —NCH3), 2.72 (1H, m, CH) and 6.68/7.18 ppm (2H, m, CONH2); δC (d6-DMSO) CH3, 41.2; CH2, 28.5, 28.5, 54.9, 54.9; CH, 46.2; C, 176.7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:12][CH2:13][CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: BrCCBr
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Nc1ccc(OCCBr)cc1[N+](=O)[O-]

Procedure:
A round-bottom flask was charged with 4-amino-3-nitrophenol (15.4 g, 0.1 mol, commercially available from Aldrich), acetone (600 mL), 1,2-dibromoethane (34.5 mL, 0.4 mol) and cesium carbonate (39 g, 0.12 mol). The mixture was refluxed 15 hours with stirring. The mixture was filtered to remove the salt, the filtrate was concentrated. Purification by the silica gel chromatography gave 4-(2-bromoethoxy)-2-nitroaniline (6.5 g). 1H-NMR (400 MHz, CDCl3): δ 7.57 (d, 1H), 7.12 (dd, 1H), 6.80 (d, 1H), 5.95 (s, br, 2H), 4.27 (t, 2H), 3.64 (t, 3H). MS (EI): 262 (MH+).
Reaction SMILES: [H-].[Na+].O.[F:4][C:5]1[CH:6]=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.4 g, 33.5 mmol) is suspended in dry DMF (10 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice:water. To above suspension is added dropwise over 15 minutes (3-Fluoro-phenyl)-methanol (2.90 ml, 27 mmol). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-chloro-1-fluoro-4-nitro-benzene (4.2 g, 24 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 4 hours. The reaction mixture is poured into 300 ml of ice:water. The resultant solid is isolated by suction filtration, washed with water (500 ml), and air dried to yield 5.5 g (20 mmol, 83%) of the clean desired material as an yellow powder.
Reaction SMILES: [Cl:1][C:2]1[S:43][C:5]2[C:6](=[O:42])[N:7](COCC[Si](C)(C)C)[C:8]3[C:9]([CH3:33])=[CH:10][C:11]([O:31][CH3:32])=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C@@H:20]([CH3:30])[CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:16][CH:15]=4)[C:13]=3[C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[NH2:22][CH2:21][C@@H:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:13]3[C:4]4[CH:3]=[C:2]([Cl:1])[S:43][C:5]=4[C:6](=[O:42])[NH:7][C:8]=3[C:9]([CH3:33])=[CH:10][C:11]=2[O:31][CH3:32])=[CH:15][CH:16]=1)[CH3:30]
Reactant: COc1cc(C)c2c(c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1)c1cc(Cl)sc1c(=O)n2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c2[nH]c(=O)c3sc(Cl)cc3c2c1-c1ccc([C@@H](C)CN)cc1
Product: Cl
Reaction time: 2 h
Yield: 183.3 %

Procedure:
To a solution of (R)-tert-butyl 2-(4-(2-chloro-8-methoxy-6-methyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (11 mg, 0.017 mmol) in CH2Cl2 (1 mL) at rt was added trifluoroacetic acid (1.0 mL) and the reaction was stirred at that temperature for 2 h. The mixture was concentrated and the residue was dissolved methanol (2 mL) and treated with NH4OH (2 mL). The resulting mixture was stirred at rt for 2 h and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired fractions were combined, concentrated and the residue was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product (7 mg, 92%) as a hydrochloride salt: 1H NMR (500 MHz, CD3OD) δ 7.52 (dd, J=7.8, 1.5 Hz, 1H), 7.47 (dd, J=7.7, 1.5 Hz, 1H), 7.32 (s, 1H), 7.31-7.22 (m, 2H), 5.30 (d, J=2.7 Hz, 1H), 3.29-3.18 (m, 3H), 2.63 (s, 3H), 1.47 (d, J=6.1 Hz, 3H); ESI MS m/z 413 [C22H21ClN2O2S I H]+.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+].[CH2:13]([OH:15])[CH3:14]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:15])=[CH:3][CH:4]=1)#[N:7].[C:1]([C:2]1[CH:9]=[CH:8][C:14]([C:13]([OH:11])=[O:15])=[CH:4][CH:3]=1)#[N:10]
Reactant: CCO
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Product: N#Cc1ccc(C(=O)O)cc1
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 66 %
Yield: 10 %

Procedure:
Terephthalonitrile (64 g, 0.5 mol) and ethanol (850.3 g) were placed in a 2 L four-neck flask, and the resultant mixture was heated to 78° C. with stirring. To the mixture, a 20% aqueous solution (20 g) of sodium hydroxide was added over six hours by use of a tube pump. After the reaction was completed, liquid chromatographic analysis revealed that the reaction mixture contained 48.2 g of p-cyanobenzamide (yield 66%) and 7.4 g of p-cyanobenzoic acid (yield 10%). The reaction mixture was cooled to 30° C., neutralized with concentrated sulfuric acid, and concentrated under reduced pressure so as to remove 508 g of ethanol. After the pressure was restored to normal pressure, the mixture was heated again to 78° C., and a 20% hydrochloric acid/ethanol solution (162.4 g) which was prepared in advance was added to the mixture over six hours by use of a tube pump. The mixture was further stirred for six hours with heat. Gas chromatographic analysis revealed that the reaction mixture contained 65.6 g of ethyl p-cyanobenzoate (yield 75%, based on terephthalonitrile) and diethyl terephthalate (yield 10%, based on terephthalonitrile). After the reaction mixture was cooled to 30° C., the mixture was neutralized with an aqueous solution of sodium hydroxide, and precipitated inorganic salt crystals were collected through filtration. After the filtrate was concentrated and water (350 g) was added thereto, the filtrate was dissolved with heat, and then cooled to 8° C. so as to reprecipitate crystals, to thereby obtain 53.6 g of ethyl p-cyanobenzoate (purity 98.0%) The obtained crude crystals were recrystallized from a solvent of a mixture of water (120 g)/ethanol (120 g), to thereby obtain 46.6 g of ethyl p-cyanobenzoate crystals (purity 99.5%; yield 53%, based on terephthalonitrile).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:11]2[CH:12]=[C:13]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].O>CN(C)C=O>[CH3:27][N:18]1[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][C:21](=[O:22])[N:16]([C:13]2[CH:14]=[CH:15][C:10]3[S:9][N:8]=[C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[O:1][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:11]=3[CH:12]=2)[C:17]1=[O:28]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4O)c3c2)c1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccsc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
To a mixture of 3-[3-(3-hydroxy-2-thienyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil(0.580 g, 1.36 mmol) in dimethylformamide is added potassium carbonate (0.230 g, 1.66 mmol). The resultant mixture is stirred 30 minutes and treated with methyl bromoacetate (0.230 g, 1.50 mmol). The mixture is stirred over a weekend at room temperature and poured into water. Filtration and drying affords the title compound as an off-white solid (0.550 g, 81.4%, mp 73-79° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH2:28][CH2:27][CH2:26]2.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[CH:28]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:27][CH2:26]2
Reactant: COC(=O)CBr
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)CC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of LDA, prepared from diisopropylamine (0.84 ml) and n-butyl lithium (3.44 ml, 1.6 M in hexane) in 10 ml of THF at -78° was added dropwise a solution of 6-methoxy-1-tetralone (0.88 g, 5.0 mmol) in 5 ml of THF in an atmosphere of nitrogen. To the stirred solution at -78° was then added methyl bromoacetate (0.5 ml, 6.0 mmole) and the mixture was allowed to warm to room temperature. Aqueous work-up and extraction with ether gave, after chromatography on silica gel, the title compound, m.p. 110°-112°.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][CH2:8][CH2:9][CH3:10])(=[O:6])O)[CH3:2].[C:11](#[N:14])[CH:12]=[CH2:13].[Na].C(O)(=O)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][CH2:12][C:11]#[N:14])([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH3:2]
Reactant: CCCCP(=O)(O)OCC
Reactant: C=CC#N
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCP(=O)(CCC#N)OCC
Temperature: 25 °C

Procedure:
15.0 g of n-butylphosphonic acid ethyl ester and 5.3 g of acrylonitrile are dissolved under argon in 25 ml of ethanol. The solution is cooled to 10°, and a solution of 1.15 g of sodium in 50 ml of ethanol is added dropwise, whereupon an exothermic reaction takes place. The mixture is then heated under reflux for one hour and cooled to room temperature, and 3.3 g of glacial acetic acid are added. The solvent is removed and the residue is taken up in dichloromethane. The resulting solution is washed with water, dried over sodium sulfate and concentrated by evaporation. The oil that remains is distilled, yielding 2-cyanoethyl(n-butyl)phosphinic acid ethyl ester having a boiling point of 120° (10-1 bar).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][O:9][C:10](Cl)=[O:11]>CCCCCC.C(OCC)(=O)C>[Cl:7][CH2:8][O:9][C:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:11]
Reactant: O=C(Cl)OCCl
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(OCCl)N1CCCCC1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Piperidine(1.06 g, 12.5 mmol) was added to a solution of chloroformic acid chloromethyl ester(645 mg, 5 mmol) in n-hexane (15 mL) at 0° C. under argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. After the ethyl acetate solution was washed successively with 1N hydrochloric acid(20 mL), water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound(796 mg, 89.6%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([C@@H:52]([N:54]2[CH2:59][C@@H:58]3[CH2:60][C@H:55]2[CH2:56][NH:57]3)[CH3:53])=[C:48]([CH3:61])[C:47]=1[CH3:62]>CC(N(C)C)=O.CCOC(C)=O>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([C@@H:52]([N:54]2[CH2:59][C@@H:58]3[CH2:60][C@H:55]2[CH2:56][N:57]3[C:7]([C:5]2[CH:4]=[N:3][CH:2]=[N:1][CH:6]=2)=[O:9])[CH3:53])=[C:48]([CH3:61])[C:47]=1[CH3:62]
Reactant: COc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3)c(C)c1C
Reactant: O=C(O)c1cncnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc([C@H](C)N2C[C@@H]3C[C@H]2CN3C(=O)c2cncnc2)c(C)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pyrimidine-5-carboxylic acid (14.9 mg, 0.12 mmol), BOP (66.3 mg, 0.15 mmol), and Et3N (34.8 μL, 0.25 mmol) are added to a solution of (1S,4S)-2-[(S)-1-(4-methoxy-2,3-dimethylphenyl)-ethyl]-2,5-diazabicyclo[2.2.1]heptane (26 mg, 0.1 mmol) in anhydrous DMA (1 mL). The reaction mixture is stirred at room temperature for 16 h, diluted with EtOAc, washed with aqueous NaOH 1N (2×8 mL) and brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by preparative thin layer chromatography eluting with CH2Cl2-MeOH—NH4OH (90-9-1) to afford a yellow oil. LC/MS: 367 (M+1).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)(=O)C>O.C(O)C>[C:1]([CH2:5][C@@H:6]([OH:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: CCOC(=O)C[C@@H](O)CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C[C@H](O)CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
To a 50 gallon reactor containing a solution of 2.2 kg (44 mol) of sodium cyanide dissolved in 40 L of demineralized water was added 7 kg (33 mol) of (S)-4-bromo-3-hydroxybutyric acid, ethyl ester (Example 3) dissolved in 8 L of ethanol. The reaction mixture was stirred for 16 hours at room temperature. Ethyl acetate (65 L) was added, the mixture agitated, and the layers were allowed to separate. The lower aqueous layer was transferred to a 50 gallon vessel containing 2.5 kg of sodium chloride and 65 L of ethyl acetate, the mixture was agitated and the layers allowed to separate, and the lower aqueous layer was cut off. The organic layers were combined and concentrated in vacuo. The residue was distilled to afford 3.1 kg of the title compound; bp 110-125° C. 0.5 mm Hg; optical rotation [α]D25 =33.1° (C=1.08, chloroform);
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Br.Cl>C(#N)C>[CH3:15][O:16][C:17](=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: COC(=O)Cc1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccccc1COc1ccccc1C
Reaction time: 0.07 h

Procedure:
5.12 g of o-cresol and 7.2. g of pulverized potash in 30 ml of acetonitrile are preheated to 60° C. and a solution of 11.06 g of 2-(bromomethyl)-phenylacetic acid methyl ester in 35 ml of acetonitrile is added dropwise over a period of 8 minutes. The reaction mixture is then stirred for 4 minutes and immediately poured onto ice-water and weakly acidified with 2N hydrochloric acid. The aqueous solution is extracted exhaustively with ethyl acetate and the combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (9:1) yields pure 2-(2-methylphenoxymethyl)-phenylacetic acid methyl ester in the form of a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[N:11]12[CH2:17][CH:15]3[CH2:14][CH:13]([CH2:18][CH:9]([N:8]([C:4]4[CH:3]=[C:2]([C:25]5[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=5)[C:19]#[N:20])[CH:7]=[N:6][CH:5]=4)[CH2:16]3)[CH2:10]1)[CH2:12]2
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: N#Cc1cccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3-cyanophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 331.0 (M+H)+, retention time 1.27 minutes.