Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][CH:8]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:9][CH:10]([O:14][C:15]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([NH2:13])=[O:12].[OH:44]CCCCCCCCCCCC(O)=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.N1C=CC=CC=1>[OH:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:8][CH2:9][CH2:10][C:11]([NH:13][NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:12].[CH3:6][O:7][CH:8]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:9][CH:10]([O:14][C:15]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([NH2:13])=[O:12]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: NCC(=O)O
Agent: CCCCCCCCC(CC(OC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1)C(N)=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)CNNC(=O)CCCCCCCCCCCO
Reaction time: 0.17 h

Procedure:
Compound 4 (3.15 g, 5.62 mmol) was dried three times by azeotropic distillation with anhydrous pyridine, 12-hydroxydodecanoic acid (3.41 g, 6.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.29 g, 6.74 mmol), 1-hydroxybenzotriazole monohydrate (2.06 g, 13.48 mmol) and anhydrous dichloromethane (50 ml) were added at room temperature under an argon atmosphere, and the mixture was stirred for 10 min. To the thus-obtained mixture was added triethylamine (2.05 g, 20.22 mmol), and the mixture was stirred at room temperature overnight under an argon atmosphere. To the obtained reaction mixture was added dichloromethane (200 ml), and the mixture was washed three times with saturated aqueous sodium hydrogen carbonate, and further washed once with saturated brine. The organic layer was fractionated, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane-methanol (95:5)+0.05% pyridine) to give hydroxydodecanamidoglycine-4,4′-dimethoxytrityloxydodecanamide (5) (2.97 g, 70%) as a colorless syrup. The instrumental analysis values of hydroxydodecanamidoglycine-4,4′-dimethoxytrityloxydodecanamide (5) are shown below.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=S)[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:12][C:4]=2[O:3]1.[NH3:31]>CO>[CH3:1][CH:2]1[C:7]([NH2:31])=[N:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: N
Reactant: CC1Oc2ccc(CCN(Cc3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2NC1=S
Solvent: CO
Product: CC1Oc2ccc(CCN(Cc3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2N=C1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
430 mg (0.962 mmol) of 2-methyl-6-[2-(3-chlorobenzyl-tert-butyloxycarbonylamino)-ethyl]-3,4-dihydro-2H-1,4-benzoxazine-3-thione is mixed with 10 ml of a solution of ammonia in methanol (7N) and stirred overnight at room temperature. The solvent is spun off, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/isopropanol). The yield is 218.6 mg (52.9%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]([C:20]3[C:21]([CH3:37])=[C:22]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:23]=[CH:24][CH:25]=3)[CH2:16][N+:17]([O-])=O)=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[Cl-].[NH4+]>O1CCCC1.CO.C(OCC)(=O)C.[Zn]>[NH2:17][CH2:16][CH:15]([C:20]1[C:21]([CH3:37])=[C:22]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=[CH:24][CH:25]=1)[C:10]1[C:9]2[C:13](=[CH:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[NH:12][CH:11]=1
Reactant: COCCOc1ccc2c(C(C[N+](=O)[O-])c3cccc(NC(=O)OCc4ccccc4)c3C)c[nH]c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(C(CN)c3cccc(NC(=O)OCc4ccccc4)c3C)c[nH]c2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
A mixture of benzyl 3-(1-(6-(2-methoxyethoxy)-1H-indol-3-yl)-2-nitroethyl)-2-methylphenylcarbamate (1.75 g, 3.48 mmol), ammonium chloride (2.79 g, 52.1 mmol), and zinc dust (3.41 g, 52.1 mmol) in tetrahydrofuran (35 mL) and methanol (35 mL) was stirred at room temperature for 4.5 hr. The mixture was diluted with ethyl acetate (40 mL) and filtered through CELITE®. The filtrate was concentrated under vacuum, and the residue was diluted with water (40 mL), basified with saturated NaHCO3 solution, and extracted with ethyl acetate (4×40 mL). The combined extract was washed with brine (40 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (1.65 g, 3.48 mmol, 100% yield) as beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=O)[CH:11]([CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH3:16])[CH:12]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NCc1ccccc1
Product: CC1CCN(C(=O)OC(C)(C)C)CCC1NCc1ccccc1

Procedure:
Racemic 4-benzylamino-5-methyl-azepane-1-carboxylic acid tert-butyl ester was prepared in the same manner from racemic 4-methyl-5-oxo-azepane-1-carboxylic acid tert-butyl ester. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.N1C=CC=[CH:24][CH:23]=1.C(OC(=O)C)(=O)C.Cl>O1CCCC1>[CH2:23]([NH:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH2:11]1)[CH3:24]
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: c1ccncc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (9.3 g) in tetrahydrofuran (100 ml) were sequentially added pyridine (8.0 ml) and acetic anhydride (6.2 ml), and the solution was stirred overnight at room temperature. To the reaction solution was added 1N hydrochloric acid, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. To a solution of the resulting N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (9.1 g) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (2.7 g), and the solution was refluxed for 2 hours. Ammonia solution (1 ml) and anhydrous magnesium sulfate were added on an ice bath, the solution was filtered, and then the solvent was evaporated in vacuo to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (8.8 g). To a solution of 4-benzyloxybenzoic acid (9.1 g) in dichloromethane (80 ml) were sequentially added oxalyl chloride (5.1 ml) and N,N-dimethylformamide (0.05 ml), the solution was stirred overnight at room temperature, then the solvent was evaporated in vacuo. To the total amount of the resulting 4-benzyloxybenzoyl chloride were sequentially added 1,4-dioxane (100 ml), N,N-diisopropylethylamine (15 ml) and ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (8.3 g), and the solution was refluxed for 30 minutes. To the reaction solution was added 1N hydrochloric acid, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the total amount of the resulting 4-benzyloxy-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (crude product) according to an analogous synthetic method to Example 22, the title compound (13 g) was obtained.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(O[N:29]1[N:37]=NC2C=CC=C[C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CNN>CN(C=O)C.C(Cl)CCl>[CH:1]1([NH:6][C:7]2[C:12]([C:13]([N:29]([CH3:30])[NH2:37])=[O:15])=[CH:11][N:10]=[C:9]3[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCn1ncc2c(NC3CCCC3)c(C(=O)O)cnc21
Agent: CNN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCCC3)c(C(=O)N(C)N)cnc21
Reaction time: 0.25 h

Procedure:
Intermediate 3 (0.10 g) was dissolved in DMF (2 ml) and treated with HBTU (0.136 g) and DIPEA (0.116 g). A separate portion of Intermediate 3 (0.10 g) was dissolved in DMF (2 ml) and treated with EDC (0.096 g) and HOBT (0.058 g). The resultant suspensions were both stirred under nitrogen for 15 min, then methyl hydrazine (0.017 g) added to each and stirring continued under nitrogen for 18 h. The mixtures were independently concentrated in vacuo and the residues partitioned between DCM and water. The organic layers were concentrated and each applied to an SPE cartridge (aminopropyl, 2 g) which was eluted with methanol, followed by 10% ammonia in methanol. The two portions of Intermediate 7 thus afforded were combined (0.16 g). LCMS showed MH+=303; TRET=2.22 min.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH3:21])[C:2]#[CH:3].C(#N)C.C(N(CC)CC)C.I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOCC>[C:33]1([C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][CH2:7][N:8]2[C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:13]=[CH:12][C:11]=3[N:10]=[C:9]2[CH3:21])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C#CCOCCCn1c(C)nc2cnc3ccccc3c21
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: Cc1nc2cnc3ccccc3c2n1CCCOCC#Cc1ccccc1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3-(2-methyl-1H-Imidazo[4,5-c]quinolin-1-yl)propyl (prop-2-ynyl) ether (4.6585 g, 16.68 mmol) from Part A, anhydrous acetonitrile (60 mL), anhydrous triethylamine (6 mL, 43.37 mmol), and iodobenzene (2.1 mL, 18.34 mmol) was heated to 80° C. with stirring. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g, 0.334 mmol), and copper(I) iodide (0.13 g, 0.667 mmol) were added and the mixture was allowed to stir for 0.5 hour. Analysis by HPLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography over silica gel, employing dichloromethane (1 L) and 98/2 dichloromethane/methanol as the eluants. The resulting green oil (5.1 g) was triturated with ether, but no solids formed. The oil was placed under high vacuum (4 torr) at room temperature. HNMR analysis of the resulting oil showed the presence of ether. The oil was further dried under high vacuum to provide 4.7 g of dark oil.
Reaction SMILES: C1COCC1.C([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:22][CH:21]=2)[C:16](=[O:33])[CH:15]=1)C1C=CC=CC=1>[Pd].CO>[OH:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:24][CH:25]=2)[C:16](=[O:33])[CH:15]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OC2CCCCO2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1cc(O)ccn1-c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Into a THF (25 mL)-MeOH (25 mL) mixed solvent solution of 4-benzyloxy-1-{4-[(2-tetrahydropyranyl)oxy]phenyl}-1H-pyridin-2-one (Step (1) of Example 12, 2.05 g, 5.4 mmols), 10% palladium-on-carbon (600 mg) was added. The atmosphere was hydrogen-substituted, and the reaction system was stirred at room temperature for 3.5 hours. The reaction liquid was filtered, the solvent was concentrated under reduced pressure, methanol was added to the resulting residue and the precipitate was recovered by filtration. Drying the same, the title compound (1.25 g, 80%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([CH3:37])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[C:30]C4C=CC=CC=4)[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])[CH3:2]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[CH3:37])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(C#Cc4ccccc4)c3)oc2C)cc1
Solvent: CCOC(C)=O
Product: C#Cc1cccc(-c2nc(CCOc3ccc(OC(C)(C)C(=O)OCC)cc3)c(C)o2)c1

Procedure:
2-Methyl-2-(4-{2-[5-methyl-2-(3-phenylethynylphenyl)oxazol-4-yl]ethoxy)phenoxy)propionic acid ethyl ester Rf=0.46 in 1:4 EtOAc:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.90 (d, 1H), 7.53-7.49 (m, 3H), 7.40-7.28 (m, 4H), 6.81-6.72 (m, 4H), 4.21-4.14 (m, 4H), 2.93 (t, 2H), 2.32 (s, 3H), 1.48 (s, 6H), 1.23 (t, 3H); MS (EI) 532.2 (M+Na)+, 510.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C(O)(=O)C>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([N:18]=[C:7]([OH:8])[C:6]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=2)[C:10]([OH:9])=[O:11])=[CH:20][CH:21]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C1OC(=O)c2c1cc([N+](=O)[O-])cc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: Cc1ccc(N=C(O)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2C(=O)O)cc1

Procedure:
2 kg (8.4 mols) of 3,5-dinitrophthalic anhydride and 897 g (8.4 mols) of p-toluidine are kept under reflux in 6.2 liters of glacial acetic acid for 3 hours. After cooling, the mixture is filtered and the residue is washed with 2 liters of water, suspended in 25 liters of water, filtered off and dried at 100° C. in vacuo.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:3]1.[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[O:1]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:3]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3ccccc3C(O)C2)cc1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCc3ccccc3C(Oc3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a solution of 1-hydroxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (10 g, 32 mmole), phenol (3.4 g, 36 mmole) and triphenylphosphine (9.5 g, 36 mmole) in benzene (300 ml), cooled with an ice bath, was slowly dropped a solution of diethyl azodicarboxylate (6.3 g, 36 mmole) in benzene (100 ml). After stirring twenty hours at ambient temperature, the reaction mixture was filtered to remove sym-dicarbethoxyhydrazine. The filtrate was concentrated to an oil which was dissolved in ether and cooled to precipitate the product and triphenylphosphine oxide. The desired product was crystallized from methanol to give a solid of 1-phenoxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (6.8 g, 33%, m.p. 155°-156° C.).
Reaction SMILES: [F:1][C:2]([F:19])([C:7]1[CH:11]=[C:10]([NH2:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>C1COCC1>[F:19][C:2]([F:1])([C:7]1[CH:11]=[C:10]([NH:12][C:27](=[O:28])[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.9 %

Procedure:
To a stirred mixture of 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-amine (300 mg, 1.08 mmol) and potassium carbonate (223 mg, 1.62 mmol) in THF (3 mL) at rt, was added a solution of phenyl chloroformate (169 mg, 1.08 mmol) in THF (2 mL) dropwise. After stirring for a further 15 h at rt, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give an oil. Purification via silica gel flash column chromatography (eluting with a gradient of 100% petroleum ether to 5% ethyl acetate in petroleum ether) afforded phenyl 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (360 mg, 84%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.55-7.62 (m, 5H), 7.39-7.43 (m, 2H), 7.29 (m, 1H), 7.14 (m, 2H), 6.91 (m, 1H); LC-MS (ESI) m/z 398 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[OH:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[N:15]1[CH2:21][C:22]#[C:23][CH2:24][O:25][CH2:26][C:27]#[N:28].CS(C)=O.FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH:13]([C@H:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[N:15]1[CH2:21][C:22]#[C:23][CH2:24][O:25][CH2:26][C:27]#[N:28])=[O:12]
Reactant: N#CCOCC#CCN1C(=O)CCC[C@@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: N#CCOCC#CCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
EDCI (288 mg, 1.50 mmol) was added to a solution of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetonitrile (118 mg, 0.50 mmol) in benzene (4 mL). The reaction mixture was cooled to 0° C. and DMSO (0.14 mL, 2.0 mmol) was added. After 5 min at 0° C., pyridinium trifluoroacetate (106 mg, 0.55 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 3 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×5 mL). The combined benzene phases were concentrated in vacuo to afford crude [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetonitrile, which was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[N:15]([C:16]4[CH:17]5[CH2:26][CH:20]([C:21]=4[CH:22]=3)[CH2:19][CH2:18]5)[CH2:14][CH2:13]2)=[CH:10][C:9]([F:27])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH3:29][N:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([NH:45][C:46]2[CH:51]=[CH:50][N:49]=[CH:48][N:47]=2)[C:31]1=[O:52].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[N:15]([C:16]4[CH:17]5[CH2:26][CH:20]([C:21]=4[CH:22]=3)[CH2:19][CH2:18]5)[CH2:14][CH2:13]2)=[CH:10][C:9]([F:27])=[CH:8][C:7]=1[C:34]1[CH:33]=[C:32]([NH:45][C:46]2[CH:51]=[CH:50][N:49]=[CH:48][N:47]=2)[C:31](=[O:52])[N:30]([CH3:29])[CH:35]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2C2CCC3C2)C1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccncn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccncn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2C2CCC3C2)C1=O
Temperature: 60 °C
Reaction time: 6 h
Yield: 58.6 %

Procedure:
A sealed tube was charged with(2-bromo-4-fluoro-6-{7-oxo-3,6-diazatetracyclo-[9.2.1.02,10.03,8]tetradeca-2(10),8-dien-6-yl}phenyl)methyl acetate 334g (400 mg, 0.9 mmol), 1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 109c (294 mg, 0.9 mmol), Na2CO3 (190 mg, 1.8 mmol), and PdCl2(dppf) (73 mg, 0.09 mmol) suspended in DMF (20 mL) and water (1 mL). The mixture was stirred at 60° C. for 6 hours. It was then partitioned between water and ethyl acetate. The organic phase was washed with water and evaporated to dryness. The residue was purified by column chromatography eluting with 15:1 methylene chloride/methanol to give 337a as a brown solid (300 mg, 58%). MS: [M+H]+ 569.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: Fc1ccc(CCl)cc1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)cc2)c1=O
Yield: 86.6 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-fluorobenzyl chloride were reacted to yield the title compound as a slightly-yellow crystalline powder (yield: 86.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([F:22])[CH:16]=1)[C:9]([C:25]1[CH:38]=[CH:37][C:28]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:27][CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1F

Procedure:
The title compound was prepared from rac-[(3-fluoro-4-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 7) and (4-bromo-phenoxy)-tert-butyl-dimethyl-silane in analogy to Example 1a): MS (ISP): 358.3 ((M−Si(CH3)2C(CH3)3)+H)+ (100%).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:8]([CH2:10][CH2:11][O:12][P:13](Cl)[Cl:14])#[N:9]>C(OCC)C>[C:8]([CH2:10][CH2:11][O:12][P:13]([Cl:14])[N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])#[N:9]
Reactant: N#CCCOP(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)N(C(C)C)P(Cl)OCCC#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Diisopropylamine (156 millimoles) was dissolved in 80 ml of diethyl ether, and then 34.7 millimoles of beta-cyanoethoxydichlorophosphine was added. The mixture was stirred at room temperature for 12 hours. After the reaction, the resulting diisopropyl ammonium chloride was separated by filtration. The ether solution was distilled to give beta-cyanoethoxymonochloro(N,N-diisopropylamino) phosphine as an oil. The yield was 73 mole%, and the product had a boiling point of 102 to 104° C. (0.08 mmHg).