Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6](=[O:24])[CH2:7][C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=23)[CH:5]=CN=[CH:2]1.CNC>O1CCCC1.O>[CH3:5][N:1]([CH3:2])[C:6](=[O:24])[CH2:7][C:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=12
Reactant: Cc1ccc(-c2nn3cccnc3c2CC(=O)n2ccnc2)cc1
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nn3cccnc3c2CC(=O)N(C)C)cc1
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A stirred slurry of 3.2 g (0.010 mole) of 3-[2-(1H-imidazole-1-yl)-2-oxoethyl]-2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (prepared from 2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid and 1,1'-carbonyldiimidazole) in 20 ml of dry tetrahydrofuran was treated with 3 ml of dimethylamine in 10 ml of dry tetrahydrofuran. After stirring for 16 hours, the reaction mixture was diluted with 100 ml of water and the precipitated solid collected by filtration (1.4 g). The crude product was purified by a liquid-solid extraction in a soxhlet using isopropyl ether as the extracting solvent. Filtration yielded 1.6 g (33.6%) of golden yellow crystals, mp 163.5°-165° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CO>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCCCCBr
Reactant: Nc1ncnc2pc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCCCn1cpc2ncnc(N)c21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
7-Amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 10, 0.5 g, 3.29 mmol) was suspended in dry DMF to which sodium hydride (160 mg, 4 mmol, 60% dispersion in mineral oil) was added under an argon atmosphere. The mixture was stirred at room temperature for 40 min and 1-bromohexane (0.56 mL, 4 mmol) was added. The reaction was continued for 3 h and the solvent was evaporated. The residue was dissolved in dichloromethane (150 mL) and washed with water (25 mL). Organic layer was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layer was dried (Na2SO4) and evaporated. The residue was purified by silica gel column (2×15 cm) chromatography eluting with dichloromethane containing 0-4% methanol. The appropriate fractions containing the desired product were evaporated to yield 0.53 g (68%), mp 220-222° C. Ir (KBr): ν690 (=P-C), 1220 (-P=CH), and 3295 (NH2) cm-1. Uv (pH 1): λmax 254 nm (ε23,700), 282 (11,500), and 314 (5200); (MeOH): λmax 266 (ε31,600); (pH 11): λmax 266 nm (ε33,300), and 330 (2200). 31 p nmr (DMSO-d6): 63.21. 1H nmr (DMSO-d6): δ 0.80(t, 3 H, CH3), 1.23 (br s, 6 H, 3CH2), 1.92 (t, 2 H, CH2), 4.24 (t, 2 H, NCH2), 8.15 and 8.23 (2s, 2 H, NH2), 8.44 (d, 1 H, C5H), and 8.86 (d, 1 H, J=58.5 Hz, C2H). Anal. Calcd. for C11H17N4P: C, 55.92; H, 7.25; N, 23.72. Found: C, 55.49; H, 7.31; N, 23.28.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[NH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1)([O-])=O>[Ni].C1COCC1>[NH2:1][C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[NH:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:11][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCC(Nc2ccccc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 26.8 %

Procedure:
To a stirred suspension of Raney nickel (510 mg) in THF (40 ml) was added 2-nitro-1-N-[1-(phenylmethyloxycarbonyl)-piperidin-4-yl]aniline (Method D) (200 mg, 0.56 mmol) and the mixture was stirred under a hydrogen atmosphere (1 atmosphere). After 15 h the mixture was filtered through Celite™, concentrated and purified by column chromatography (eluting with 25% EtOAc/DCM) to give the title compound as an oil (50 mg, 0.15 mmol); NMR: 1.3 (m, 2H), 1.9 (m, 2H), 3.0 (m, 2H), 3,3 (m, 2H),3.9 (m, 1H), 4.1 (d, 1H), 4.45 (br s, 2H), 5.05 (s, 2H), 6.4 (m, 4H) and 7.3 (m, 5H); MS: 326.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[S:22][CH2:23][C:24]([O:26]C)=[O:25])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[OH-].[Na+].Cl>CO>[CH3:14][C:11]([C:9]1[CH:8]=[C:7]([CH2:15][CH2:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[S:22][CH2:23][C:24]([OH:26])=[O:25])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:10]=1)([CH3:12])[CH3:13]
Reactant: COC(=O)CS[C@@H]1CCC[C@H]1CCc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(CC[C@@H]2CCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 300 mg (0,767 mmole) of the title product of Example 39 in 5 ml methanol is added 5 ml of 1M aqueous sodium hydroxide. After stirring at room temperature, the mixture is acidified with dilute aqueous hydrochloric acid and extracted with diethyl ether. The organic layer is dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate, hexane, and acetic acid as eluents gives the title compound.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(CN2CCc3ccccc3C2c2ccccc2)cc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3ccccc3C2(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an ice bath under argon flow, a solution of 1.07 M phenylmagnesium bromide in THF (33.2 mL) was added dropwise to a solution of 2-benzyl-1-phenyl-3,4-dihydroisoquinoline hydrobromate (8.95 g) in THF (80 mL) over 1 hour. The mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the mixture which was then extracted with EtOAc. The extract was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-benzyl-1,1-diphenyl-1,2,3,4-tetrahydroisoquinoline (1.81 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1.N(C([O-])=O)=NC([O-])=O>O1CCCC1>[C:53]([O:52][C:50]([N:47]1[CH2:48][CH2:49][N:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[O:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=3)[C:3]2=[O:17])[CH2:45][CH2:46]1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: O=C1C(O)CCN1c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCN(c3ccc(C(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 241 mg (0.983 mmol) 3-hydroxy-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one, 15 mL dry tetrahydrofuran, 645 mg (2.45 mmol) triphenylphosphine, and 328 mg (1.18 mmol) N-(2-hydroxyphenyl)-4-t-butoxycarbonyl-piperazine. A solution of 398 mg (1.97 mmol) disopropyl azodicarboxylate in 10 mL dry tetrahydrofuran was added dropwise over 5 minutes, and the reaction stirred at room temperature overnight. The reaction was quenched with aqueous sodium bicarbonate solution, separated, and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was chromatographed on silica using hexane/ethyl acetate as eluant to afford 320 mg (64%) of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:13]([CH3:19])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:29](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:13]([CH3:19])=[CH:14][C:15](=[O:18])[N:16]([CH3:29])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cc(=O)[nH]cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cc1cc(=O)n(C)cc1C(=O)CC(c1ccc(Br)cc1)c1ccccc1C

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-4-methyl-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=424.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:34]=[CH:33][C:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:34]=[CH:33][C:21]4[CH2:22][CH2:23][N:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(CC(=O)O)CC4)no2)cc1C#N
Temperature: 40 °C
Yield: 88.9 %

Procedure:
A mixture of ethyl [7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]acetate (Preparation 47) (43 mg, 0.09 mmol), aqueous sodium hydroxide (2M, 430 μL, 0.86 mmol) and ethanol (4.3 ml) was heated at 40° C. for 1 h. The reaction mixture was cooled to room temperature and concentrated. The residue was taken up in water, which was then acidified to pH 6 with acetic acid. The aqueous phase was extracted with EtOAc (2×20 ml) and the combined organic fractions concentrated to give a white solid, which was then triturated with EtOAc to give the title compound as a white solid (36 mg, 0.08 mmol). δH (d6DMSO, 400 MHz): 8.50 (1H, d), 8.41 (1H, dd), 7.85-7.80 (2H, m), 7.55 (1H, d), 7.32 (1H, d), 4.98 (1H, septet), 3.00-2.91 (6H, m), 2.75-2.66 (4H, m), 1.39 (6H, d); MS (ES−): C24H24N4O4 requires 432; found 431 [M−H]+.
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][C@@:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C1C=CN=C(C2C=[CH:42][CH:43]=[CH:44]N=2)C=1.C1(B(O)O)CC1.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:42]1([N:22]2[CH:23]=[CH:24][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:32])[CH3:33])([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[CH:20][C:21]2=[O:25])[CH2:43][CH2:44]1
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Product: C[C@@H](c1ccc(-c2ccn(C3CC3)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 70 °C
Reaction time: 22 h
Yield: 85 %

Procedure:
A mixture of (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1.683 g, 3.77 mmol, 1.0 equiv), Cu(OAc)2 (0.692 g, 3.81 mmol, 1.01 equiv), bipyridine (0.599 g, 3.83 mmol, 1.02 equiv), cyclopropylboronic acid (0.681 g, 7.93 mmol, 2.10 equiv) and Na2CO3 (0.890 g, 8.40 mmol, 2.23 equiv) in dichloroethane (40 mL) was stirred at 70° C. for 22 h under air. The reaction mixture was quenched with satd aq NH4Cl, diluted with CH2Cl2, dried over Na2SO4. After the solvent was removed under reduced pressure, the residue was purified by chromatography on silica gel eluted with MeOH/CH2Cl2 to afford 1.560 g (85%) of (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one. LC-MS tR=1.41 min in 3 min chromatography, m/z 429, 487 (MH+); 1H NMR (400 MHz, CD3OD) δ 7.52 (d, J=7.0 Hz, 1H), 7.29-7.18 (m, 7H), 6.92 (d, J=8.2 Hz, 2H), 6.54 (d, J=1.8 Hz, 1H), 6.47 (dd, J=7.3, 1.8 Hz, 1H), 5.47 (q, J=7.0 Hz, 1H), 3.27-3.21 (m, 1H), 2.95-2.91 (m, 1H), 2.48-2.33 (m, 2H), 2.15-2.08 (m, 1H), 2.07 (s, 2H), 1.42 (d, J=7.0 Hz, 3H), 1.20 (s, 3H), 1.05-1.00 (m, 2H), 0.87 (s, 3H), 0.83-0.79 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 166.17, 155.63, 152.88, 144.03, 142.27, 138.90, 136.91, 129.71, 128.70, 128.58, 127.67, 126.09, 116.08, 107.10, 85.19, 71.49, 55.13, 54.62, 37.44, 33.24, 32.71, 31.86, 30.03, 15.60, 7.27. (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (ca. 1.5 g) and isopropyl acetate (30 mL) was heated in a 120° C. oil bath, affording a homogeneous solution. Heating was discontinued and the resulting solution was slowly stirred while slowly cooling to rt in the oil bath overnight. The solids were filtered and washed with isopropyl acetate, dried at room temperature under high vacuum affording crystalline solid Mp 91-94° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CC[N:27]([CH:31]([CH3:33])[CH3:32])C(C)C.C1(N)CC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([NH:27][CH:31]1[CH2:33][CH2:32]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1c(C(=O)NC2CC2)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of 5-t-butyl-2-methoxy-3-nitrobenzoic acid (759 mg, 3 mmol) in 18 mL DCM, oxalyl chloride (1.8 mL, 15 mmol) was added. After stirring at rt for 2 hr the reaction mixture was concentrated to dryness. The resulting acid chloride was dissolved in 30 mL DCM, and DIEA (2.6 mL, 15 mmol) and cyclopropyl amine (0.83 mL, 12 mmol) were added. Stirring was continued overnight at rt, after which DCM was added to the reaction mixture. After aq. sodium bicarbonate work-up, column chromatography purification was performed on ISCO Optix (3×12 g silica gel column) using DCM. 678 mg pure product was isolated as pale yellow solid. Calculated mass=292. Observed mass=295
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].I[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:1][C:2]#[C:3][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: FC(F)(F)Oc1ccc(I)cc1
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(OC(F)(F)F)cc1

Procedure:
In analogy to the procedure described for example 8 a], tert-butyl 2-propynylcarbamate was reacted with 1-iodo-4-trifluoromethoxy-benzene in the presence of PdCl2(Ph3P)2 and cuprous iodide to give the title compound as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[CH3:12][N:13](C)C=O>C(OCC)C.C(=O)(O)[O-].[Na+].[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:12]#[N:13])[CH3:11]
Reactant: CCOc1ccc(C)cc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCOCC
Product: CCOc1ccc(C)cc1C#N
Temperature: 95 °C
Yield: 33 %

Procedure:
To a solution of 2-bromo-1-ethoxy-4-methyl-benzene (940 mg, 4.37 mmol) in dimethylformamide (5 mL) at room temperature was added zinc cyanide (513.1 mg, 4.37 mmol). The reaction mixture was degassed by passing argon through for 2 h before tetrakis(triphenylphosphine)palladium (505 mg, 0.437 mmol) was added. The reaction mixture was heated at 90-100° C. under argon for 12 h. The slurry reaction mixture was taken up in diethyl ether (10 mL) and sodium bicarbonate solution (2 mL). The product was extracted with diethyl ether (2×30 mL). The organic layers were washed with water (1×5 mL), brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 10% ethyl acetate in hexanes yielded 2-ethoxy-5-methyl-benzonitrile (232 mg, 33%).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:19])[C:10]2[C:20]([CH3:27])=[C:21]([O:25][CH3:26])[CH:22]=[C:23]([OH:24])[C:9]=2[CH2:8][S:7][CH2:6]1)=O>CO.C(N)C=C>[CH2:16]([NH:17][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:19])[C:10]2[C:20]([CH3:27])=[C:21]([O:25][CH3:26])[CH:22]=[C:23]([OH:24])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:2])[CH:15]=[CH2:14]
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCC(=S)N1
Solvent: CO
Solvent: C=CCN
Product: C=CCNC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCC(=S)N1
Temperature: 50 °C
Yield: 147.5 %

Procedure:
A solution of 124 mg of (R)-15-hydroxy-13-methoxy-12-methyl-11-oxo-6-thioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclo-tridecine-4-carboxylic acid methyl ester in a mixture of 1.5 ml of methanol and 1.5 ml of allylamine was heated to 50° C. for 2.5 h. The solution was evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (2:1, v/v) as eluent, and the purified product was crystallized from ethyl acetate/hexane to afford 97 mg of (R)-15-hydroxy-13-methoxy-12-methyl-11-oxo-6-thioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid allylamide as a white solid.
Reaction SMILES: Br[CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[Mg].[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)=[O:9].[NH4+].[Cl-]>CCOCC.C1COCC1>[CH2:3]([CH:2]([CH2:5][CH3:6])[CH:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=1)[OH:9])[CH3:4]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CCC(Br)CC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CC)C(O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 3-bromopentane (0.331 mol) in (C2H5)2O (200 ml) was added dropwise to a solution of magnesium turnings (0.331 mol) in (C2H5)2O, the mixture was stirred at RT for 2 hours and then cooled to 0° C. A solution of N-(4-formylphenyl)acetamide (0.11 mol) in THF (400 ml) was added dropwise and the mixture was stirred for 10 minutes. The mixture was poured into aqueous NH4Cl and extracted with EtOAc. The organic layer was dried, filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated, yielding 13.5 g (52%) of (±)-N-[4-(2-ethyl-1-hydroxybutyl)phenyl]acetamide (interm. 13).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1.[CH3:29][Si:30]([CH3:67])([CH2:46][CH2:47][C:48]([F:66])([F:65])[C:49]([F:64])([F:63])[C:50]([F:62])([F:61])[C:51]([F:60])([F:59])[C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])[CH2:31][CH2:32][CH2:33][CH2:34]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:67][Si:30]([CH3:29])([CH2:46][CH2:47][C:48]([F:65])([F:66])[C:49]([F:63])([F:64])[C:50]([F:62])([F:61])[C:51]([F:59])([F:60])[C:52]([F:57])([F:58])[C:53]([F:54])([F:55])[F:56])[CH2:31][CH2:32][CH2:33][CH2:34][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[N:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:28])[CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])=[CH:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reactant: C[Si](C)(C)C[Si](C)(C)CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)C[Si](C)(C)CCCCCCOc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of 4-{5-[6-(dimethyltrimethylsilanylmethyl-silanyl)-hexyloxy]-pyrimidin-2-yl}-phenol (0.083 g, 0.200 mmol), toluene-4-sulfonic acid 4-[dimethyl-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-octyl)-silanyl]-butyl ester (0.126 g, 0.200 mmol) and cesium carbonate (0.078 g, 0.24 mmol) in DMF (10 ml) was stirred at room temperature for 24 h. The reaction mixture was washed with water and the organic layer extracted into ethyl acetatelhexane (3×20 ml, 1:1). The combine extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[CH:29]([NH2:32])([CH3:31])[CH3:30]>CO>[OH:21][CH:19]([CH2:20][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:18][O:17][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[CH:15]=[C:6]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=3)[O:7]2)=[CH:12][CH:11]=1
Reactant: CC(C)N
Reactant: COc1cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc(OC)c1OC
Solvent: CO
Product: COc1cc(-c2cc(=O)c3ccc(OCC(O)CNC(C)C)cc3o2)cc(OC)c1OC

Procedure:
3′,4′,5′-Trimethoxy-7-(2,3-epoxy-propoxy)-flavone, 31 (1.2 g, 3 mmol) and iso-propyl amine (0.78 mL, 9.3 mmol) in dry methanol (120 mL) were reacted in a similar manner to that described under 34 to afford 41. Yield 900 mg (65%); mp 106-107° C.; MS (FAB) 444 (M++1); IR (KBr) 3394, 1631; 1H NMR (200 MHz, CDCl3) δ 8.09 (d, J=9.5 Hz, 1H), 7.10 (s, 2H), 7.10-6.99 (m, 2H), 6.71 (s, 1H), 4.16-4.09 (m, 3H), 3.96 (s, 6H), 3.93 (s, 3H), 2.95-2.82 (m, 3H), 1.14 (d, J=6.2 Hz, 6H).