Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[Br:19]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:19][CH:9]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:18])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: BrBr
Reactant: CCOC(=O)CCCCC(=O)c1ccc(F)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Ethyl 6-(4-fluorophenyl)-6-oxohexanoate (14.0 g) was dissolved in methylene chloride (100 ml), and bromine (8.87 g) was added dropwise with stirring at room temperature. After an hour of stirring at room temperature, a 10% aqueous solution of sodium sulfite was carefully added until disappearance of the red color of bromine, and the mixture was then extracted with diethyl ether (100 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 5-bromo-6-(4-fluorophenyl)-6-oxohexanoate as an oil (17.6 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[N:32]([CH3:33])[CH3:31])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:28][CH2:29][OH:30])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CNC
Reactant: O=C(O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Product: CN(C)C(=O)c1ccc(N(CCO)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Yield: 50 %

Procedure:
Following the procedure of Example 91, 3-chloro-4-(N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and dimethylamine were reacted to give 220 (yield 50%). MS: (ESI+) 471.1
Reaction SMILES: [Br:1]C1C=C2C(C(C=O)=CN2)=CC=1.C(O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31])C=C>>[Br:1][C:25]1[CH:24]=[C:23]2[C:19]([C:20]([N:29]=[C:30]=[O:31])=[CH:21][N:22]2[C:26]([NH2:28])=[O:27])=[CH:18][CH:17]=1
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: NC(=O)n1cc(N=C=O)c2ccc(Br)cc21

Procedure:
was prepared from 6-bromo-1H-indole-3-carbaldehyde using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:33]C(=O)OCC5C=CC=CC=5)[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1>C1COCC1.CO.[Pd]>[NH2:33][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[O:23][C:20]1([CH2:21][CH2:22][N:17]([C:15]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:12]4[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=4)[N:6]=3)=[O:16])[CH2:18][CH2:19]1)[CH2:31][C:30]2=[O:32]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(NC(=O)OCc4ccccc4)ccc2O3)nc2c(OC)cccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N)ccc2O3)nc2c(OC)cccc12

Procedure:
3.78 g of benzyl {1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}carbamate was dissolved in 20 mL of THF and 40 mL of MeOH, and hydrogenated on 10% Pd/C at room temperature. Pd/C was removed through filtration, and the filtrate was concentrated to obtain the intended compound. 1H-NMR (CDCl3) δ: 7.77 (1H, dd, J=8.5, 1.2 Hz), 7.47 (1H, t, J=8.0 Hz), 7.17 (1H, s), 7.15 (1H, d, J=2.9 Hz), 7.08 (1H, dd, J=7.8, 1.0 Hz), 6.91 (1H, dd, J=8.8, 2.9 Hz), 6.85 (1H, d, J=8.8 Hz), 4.56 (1H, d, J=13.2 Hz), 4.16-4.08 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.63-3.53 (3H, m), 3.34 (1H, td, J=12.8, 3.3 Hz), 2.76 (1H, d, J=16.5 Hz), 2.70 (1H, d, J=16.5 Hz), 2.20 (1H, dd, J=13.9, 2.7 Hz), 2.05 (1H, dd, J=13.9, 2.7 Hz), 1.88-1.78 (2H, m). MS [M+H]+=448.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(CC(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(CC(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
To methyl 4-[(2-{1-[4-hydroxy-5-(4-isobutylphenyl)-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.129 mmol, 57.7 mg), methanol (2.5 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.643 mL) was added at room temperature. After 15 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (Seq., 0.643 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (25.6 mg, yield 46%).
Reaction SMILES: C(OC([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[N:16]([CH2:19][CH3:20])[CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>CCO.O>[CH2:19]([N:16]1[C:12]2[C:13]3[CH2:14][CH2:15][NH:6][CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[CH:18]=[CH:17]1)[CH3:20]
Reactant: CCOC(=O)N1CCc2sc3ccn(CC)c3c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ccc2sc3c(c21)CCNCC3
Temperature: 100 °C

Procedure:
To a stirred solution of the product from step (a) (0.060 g, 0.21 mmol) in EtOH (2 ml) was added 40% aqueous KOH (2 ml). The reaction mixture was heated to 100° C. until LCMS indicated that the reaction was complete (usually 16-32 hours). The reaction mixture was cooled to RT, diluted with water (30 ml), and extracted with DCM (3×). The combined DCM extracts were dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product. Purification by preparative HPLC gave the title compound as a tan solid. 1H NMR (CD3)2CO™ 6.82 (d, J=2.7 Hz, 1H), 6.14 (d, J=2.7 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.01-2.92 (m, 6H), 2.86-2.78 (m, 2H), 1.35 (t, J=7.2 Hz, 3H); MS: ESI (positive): 221 (M+H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=O>>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][NH:10][C@H:7]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[CH2:8][OH:9]
Reactant: NC(CO)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Product: OC[C@H](NCc1ccc2ccccc2c1)c1ccccc1

Procedure:
Using 1.00 g (7.29 mmol) of (R)-phenylglycinol ((R)-VIII-2) and β-naphthoaldehyde, a similar operation was carried out to obtain (R)-N-(β-naphthyl)methyl-2-phenylglycinol (2.01 g) ((R)-II-3) quantitatively. ##STR317##
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:14])[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4]1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:17]([O:1][CH2:2][C:3]1([CH3:14])[CH2:7][O:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(CO)COC(c2ccccc2)=N1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(COCc2ccccc2)COC(c2ccccc2)=N1
Reaction time: 16 h

Procedure:
A suspension of 4-hydroxymethyl-4-methyl-2-phenyloxazoline (19.1 grams, prepared by the method described in J. Amer, Chem. Soc. 1945, 67, 1069) in toluene (200 milliliters) was added slowly to a stirred suspension of sodium hydride (2.4 grams) in toluene (50 milliliters). Some warming was necessary to initiate the reaction. The mixture was then heated under reflux for 2 hours with stirring. Benzyl chloride (13.0 grams) was added to the mixture over a period of 10 minutes. The mixture was heated under reflux for a further 5 hours and then allowed to stand at room temperature for 16 hours. The mixture was washed with water (3 × 200 milliliters), dried (MgSO4) and evaporated under reduced pressure. The residue was distilled in vacuo to give the desired product, boiling point 147°-149°C at 0.3 Torr.
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.[OH-].[Na+].[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[CH:19]=[CH:20][CH2:21][Cl:22])([O-:15])=[O:14]>O.C(O)C>[ClH:22].[N+:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[CH:19]=[CH:20][CH2:21][N:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2]1)([O-:15])=[O:14]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=[N+]([O-])c1cccc(C=CCCl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(C=CCN2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 51.4 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. A solution of 5.68 grams of isoindoline hydrochloride and 2.86 grams of sodium hydroxide in 15 milliliters of water is added to a solution of 6.8 grams of m-nitrocinnamyl chloride in 160 milliliters of ethanol, and the mixture is stirred for 10 hours at room temperature. After completion of the reaction, the reaction product is concentrated, and the residue is extracted with chloroform. The extract is then purified by silica gel column chromatography, following which the resulting oily product is converted to a hydrochloride in a customary manner and recrystallized from ethanol to obtain 5.6 grams (yield 52%) of N-(m-nitrocinnamyl)-isoindoline hydrochloride as crystals having a melting point of 208°-210° C. (decomposition).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[C:35]([F:43])[CH:34]=1>>[F:43][C:35]1[CH:34]=[C:33]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)[CH:38]=[CH:37][C:36]=1[O:39][CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: CC(C)Oc1ccc(Br)cc1F
Product: CC(C)Oc1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3c2)cc1F
Yield: 15.7 %

Procedure:
Following the General Procedure-3, the titled compound (25 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromo-2-fluoro-1-isopropoxybenzene (81 mg, 0.35 mmol) as a white solid. M.P.: 124-128° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.81 (d, J 1.4, 1H), 7.53-7.45 (m, 2H), 7.35-7.27 (m, 2H), 7.05 (t, J 8.6, 1H), 4.58 (septet, J 6.1, 1H), 4.15 (d, J 10.4, 2H), 3.20-3.10 (m, 1H), 2.99 (t, J 11.7, 2H), 2.15 (dd, J 2.8, 13.4, 2H), 1.97-1.86 (m, 2H), 1.56 (s, 9H), 1.39 (d, J 6.1, 6H).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8](O)[CH3:9]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[CH3:9]
Reactant: O=C1C=CC(O)N1
Reactant: CCO
Product: CCOC1C=CC(=O)N1

Procedure:
A mixture of 2.3 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 140 cm3 of ethanol and 100 g of Amberlite resin IR-120 (H) is taken to reflux for 30 minutes. After allowing to cool, filtering off the resin and distilling the ethanol off under reduced pressure, 2.76 g of the expected product is obtained, m.p. 50°-52° C.
Reaction SMILES: [SH2:1].[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH:14]=[N:15][C:16]([C:17]#[N:18])=[C:6]2[C@@H:5]2[CH2:19][CH2:20][N:4]12>N1C=CC=CC=1.C(N(CC)CC)C>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH:14]=[N:15][C:16]([C:17](=[S:1])[NH2:18])=[C:6]2[C@@H:5]2[CH2:19][CH2:20][N:4]12
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reaction time: 70 h
Yield: 67 %

Procedure:
A stream of hydrogen sulphide was conducted for 1/2 hr. through a solution of 5.0 g (0.020 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile in 100 ml of pyridine and 1 ml of triethylamine. The dark brown solution was left to stand for 70 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and extracted. The pale yellow product was chromatographed over silica gel with ethyl acetate as the eluent, stirred vigorously in ether for 16 hrs. and subsequently filtered off under suction. There were obtained 3.8 g (67%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-thiocarboxamide as pale yellow crystals; m.p. 227-230° and [α]D20 =-473.7° (DMF, c=1%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 0.83 h
Yield: 92.9 %

Procedure:
(S)-(1-Benzyl-2-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (8.10 g, 15.1 mmol, Example 51) was dissolved in CH2Cl2 (50 mL) under nitrogen at ambient temperature. To this solution was added trifluoroacetic acid (12 mL). The resulting reaction mixture was stirred for 50 minutes, then concentrated in vacuo. The viscous pale-amber oil obtained was mixed with 50 mL of saturated aqueous NaHCO3 solution and stirred for 10 minutes, 50 mL of CH2Cl2 was then added. The resulting mixture was stirred until bubbling ceased. The two layers were separated, organic layer was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording 6.11 g (92%) of the pure titled compound as a off-white foam: mp 44-51° C. APCI-MS m/z 436.3 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1>O1CCOCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: N#Cc1ccc(N)nc1
Solvent: C1COCCO1
Product: N#Cc1ccc2nc(-c3ccc(F)cc3)cn2c1
Yield: 46.1 %

Procedure:
2-Bromo-1-(4-fluoro-phenyl)-ethanone (2.08 g, 9.6 mmol) and 6-amino-nicotinonitrile (1.14 g, 9.6 mmol) were heated under reflux in 50 ml dioxane for 13 hours. After cooling the solid was filtered and purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 1.05 g (46%) of the desired product. MS: M+H+=238.04.
Reaction SMILES: [CH3:1][C@@H:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>CO>[CH2:16]([NH:18][C:19](=[O:20])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:17]
Reactant: CCN=C=O
Reactant: CC[C@@H](C)Oc1ccc(OCCO)cc1
Solvent: CO
Product: CCNC(=O)OCCOc1ccc(O[C@H](C)CC)cc1

Procedure:
Following the procedure of Example 9, the above alcohol (0.42 g, 2.0 mmol) is reacted with ethyl isocyanate (0.18 ml, 2.2 mmol) to give O-2-[(R)-4-(1-methylpropoxy)phenoxy]ethyl N-ethylcarbamate, specific rotation [α]D20 =-19.103° (c=10% in methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[N:8][N:9]([C:26]2[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:28][CH:27]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2cncnc2)n[nH]c1C1CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)c1c(-c2cncnc2)nn(-c2ccc(OC(F)(F)F)cc2)c1C1CC1
Yield: 29 %

Procedure:
In analogy to the procedure described in Example 162C], 5-cyclopropyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid ethyl ester (Example 177B]) and 4-(trifluoromethoxy)benzeneboronic acid gave the title compound as a yellow oil (29%). MS: 419.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].N1C2C(=CC=CC=2)[CH:37]=[CH:36][C:35]=1N>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]3[C:18](=[CH:35][CH:36]=[CH:37][CH:20]=3)[N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:7]2=[O:33]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: Nc1ccc2ccccc2n1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc2ccccc2n1

Procedure:
The product from Example 11, Part D (200 mg, 0.6 mmol) and quinolin-2-ylamine (131 mg, 0.91 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E, using CH2Cl2 in place of THF in the reaction and EtOAc in the workup, and without crystallization (220 mg, 80%). 1HNMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.87 (d, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.66 (m, 2H), 7.48 (t, J=7 Hz, 1H), 7.41 (m, 1H), 7.32 (m, 2H), 7.16 (t, J=9 Hz, 1H), 7.01 (t, J=7 Hz, 2H), 5.30 (d, J=15 Hz, 1H), 4.71 (m, 1H), 4.25 (d, J=15 Hz, 1H), 2.59 (m, 2H), 1.98 (m, 2H). MS: m/z (MH+) 458.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]([O:23][C:24]([NH:26][C:27]([CH3:45])([CH3:44])[CH2:28][C:29]([NH:31][C@@H:32]1[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[NH:34][C:33]1=[O:43])=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[CH2:37][CH2:38][C@@H:32]([NH:31][C:29](=[O:30])[CH2:28][C:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:44])[CH3:45])[C:33]2=[O:43])=[CH:4][CH:5]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(=O)Oc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from 4'-bromomethyl-2-acetoxy-1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1H NMR (200 MHz,CDCl3): 1.38 (s,6H), 1.45 (s,9H), 1.85 (m,1H), 2.02 (s,3H), 2.35-2.65 (m,5H), 4.52 (m,1H), 4.84 (d,15 Hz,1H), 5.30 (d,15 Hz,1H), 6.71 (d,7 Hz,1H), 7.1-7.4 (m,12H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:12]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].CCN(C(C)C)C(C)C.[Cl:36][CH2:37][C:38](Cl)=[O:39].Cl>ClCCCl>[CH3:18][C:14]1([CH3:17])[C:15](=[O:16])[N:11]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:9])[CH3:10])=[C:2]([NH:1][C:38](=[O:39])[CH2:37][Cl:36])[CH:3]=2)[C:12](=[O:26])[N:13]1[CH2:19][C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1
Reactant: CC(C)c1ccc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)cc1N
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)cc1NC(=O)CCl
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1.37 mg (3.89 mmol) 3-(3-amino-4-isopropyl-phenyl)-5,5-dimethyl-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione and 528 mg (4.08 mmol) Hünig's base were dissolved in 50 ml 1,2-dichloroethane. The mixture was cooled to −20° C. and treated with a solution of 439 mg (3.89 mmol) chloroacetylchlorid in 20 ml 1,2-dichloroethane. After stirring 1 h at 0° C., 25 ml ethanolic hydrochloric acid were added and the mixture evaporated to dryness. The raw material, containing huening's base hydrochloride was used without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:7]#[CH:8])[CH3:6])[CH:2]=C.F[P-](F)(F)(F)(F)F.[C:22]1(C)C=CC=CC=1>>[CH3:6][C:5]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7]([CH:8]=[CH2:22])=[CH:2][CH2:1][O:4]1
Reactant: C#CC(C)(OCC=C)c1ccccc1
Reactant: Cc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Product: C=CC1=CCOC1(C)c1ccccc1

Procedure:
A solution of 2-allyloxy-2-phenylbut-3-yne (368 mg, 1.97 mmol) and the allenylidene complex (p-cymene)RuCl(PCy3)(═C═C═CPh2)+PF6− (43 mg, 0.0485 mmol, 2.5 mol %) in toluene (10 ml) is stirred for 24 hours at 80° C. under nitrogen. The solvent is evaporated and the crude product is purified by flash chromatography using ether:pentane (1:10) as the eluent. The title compound was obtained as a yellowish liquid (283 mg, 77%). 1H NMR (200 MHz, CDCl3): d=1.79 (s, 3H, CH3); 4.76 (m, 2H, J=0.8, OCH2); 5.02 (d, 1H, J=11.2, ═CH2); 5.06 (d, 1H, J=17.8, ═CH2); 5.98 (m, 1H, C═CH); 6.21 (ddd, 1H, J=17.8, 11.2 and 0.8, ═CH); 7.20-7.47 (m, 5H, Ph). 13C NMR (50 MHz, CDCl3): d=24.4 (CH3); 73.1 (OCH2); 89.8 (C); 117.1 (═CH2); 124.3 (═CH); 126.1 (Ph); 128.3. (═CH); 128.6, 128.9 (Ph); 144.5 (C); 144.7 (C Ph). IR (NaCl windows): 3088, 3060, 3029, 2979, 2832, 2837, 1821, 1644, 1620, 1596, 1492, 1448,1370, 1344, 1239, 1201, 1139, 1068, 1021, 991, 913, 865, 807, 763, 701. MS (rel. Intensity): 186 ([M+], 8); 172 (19); 171 (100); 153 (15); 144 (7); 143 (43); 142 (19); 128 (50); 127 (11); 115 (27); 109 (19); 105 (23); 91 (20); 81 (12); 79 (14); 78 (11); 77 (54); 76 (7); 66 (15); 65 (26); 63 (13); 55 (13); 53 (10); 52 (7); 51 (33); 50 (9); 43 (49); 40 (12); 39 (30); 27 (11). C13H14O (186.27): calcd. C, 83.83, H, 7.66; found: C, 83.54, H, 7.58.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[CH2:8])[CH3:2].[Cl:10][C:11]([Cl:16])(Cl)[C:12](Cl)=[O:13]>C(OCC)C.COCCOC.[Cu].[Zn]>[Cl:10][C:11]1([Cl:16])[C:12](=[O:13])[CH2:8][CH:7]1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: C=CCCC(=O)OCC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)CCC1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
A mixture of 4-pentenoic acid ethyl ester (7.07 g, 55.2 mmol) and zinc-copper couple (10.2 g, 140 mmol) in diethyl ether (170 mL) and 1,2-dimethoxyethane (25 mL) was treated dropwise with trichloroacetyl chloride (25 g, 140 mmol). The mixture was stirred at room temperature for 3 days. The reddish heterogeneous reaction mixture was filtered through a pad of celite and the pad was washed with 300 mL Et2O. The filtrate was concentrated to about one half the original volume and the organic phase was washed with two 150 mL portions of H2O and one 150 mL portion of sat NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to yield a brown liquid. The material was purified by vacuum distillation (90-100° C. @0.044 torr) to yield the title compound (10.49 g, 80%) as a light yellow liquid: GC purity 95.8% (ret. time, 4.92 min).