Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][NH:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]>O.C(OCC)C>[C:8]1([C:14]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][N:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(-c2c[nH]nc2-c2ccccc2)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(-c2cn[nH]c2-c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Sodium hydride (1.57 g of 50% dispersion, 32 mmol) was washed twice with hexanes, covered with DMF (100 mL), and a mixture of 3,4-diphenyl-lH-pyrazole and 4,5-diphenyl-lH-pyrazole (6.00 g, 27 mmol) was added. After gas evolution had ceased, the mixture was stirred for 10 minutes before adding methyl 8-bromooctanoate (7.10 g, 30 mmol). The mixture was stirred at room temperature for 40 minutes, diluted with water, and extracted with diethyl ether (3 times). The combined extracts were washed with water (3 times), dried over sodium sulfate, and concentrated in vacuo to leave an oil. Repeated chromatography on a column of silica gel using a mixture of hexanes and diethyl ether (2:1) as eluant provided methyl 3,4-diphenyl-lH-pyrazole-1-octanoate (6.11 g, 59%) as an oil. MS(CI): m/e =377 (MH+).
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[CH3:11][C:12]1([CH2:15][CH:16]([CH3:23])[CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[O:14][CH2:13]1>CCOCC.CCCCCC>[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[CH2:11]=[C:12]([CH2:15][CH:16]([CH3:23])[CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[CH2:13][OH:14]
Reactant: CCCC(C)CC(C)CC1(C)CO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCNCC
Product: C=C(CO)CC(C)CC(C)CCC
Reaction time: 0.17 h

Procedure:
An ice-cold solution of diethylamine (3.48 g, 4.9 ml, 47.55 mmol, dried with KBr) in 10 ml of anhydrous ether was prepared. Next, 19.1 ml of a 2.5M solution of n-butyllithium in hexane was added to the diethylamine solution with stirring under a nitrogen atmosphere. After 10 minutes, a solution of 2,4,6-trimethyl-1,2-epoxynonane (6) (3.50 g, 19.0 mmol) in 10 ml of anhydrous ether was added to the reaction mixture and this mixture was refluxed for one hour. Progress of the reaction was checked by withdrawing samples, quenching with water, and analyzing by TLC. Reaction time was determined to ensure total consumption of the epoxide. Upon completion, the reaction mixture was cooled and poured into ice water. The organic layer was separated and the aqueous layer was saturated with solid sodium chloride and extracted with ether. The combined organic layers were washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate solution, water, and brine. the solution was dried over sodium sulfate and solvent was removed in vacuo. Vacuum distillation at 85° -90° C. yielded 2-methylene-4,6-dimethylnonan-1-ol (7).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:7][CH:8]=2)[NH:3]1.FC(F)(F)C(O)=O>>[NH:15]1[CH2:14][CH2:13][CH:12]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][NH:11][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)NC(=O)NC3)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2ccc(C3CCNCC3)cc2N1
Yield: 95 %

Procedure:
Following the same procedure adopted for the synthesis of 5, treatment of compound 23 with trifluoroacetic acid afforded the title compound 6 as a dark brown gum (95%). IR (KBr) νmax. cm−1: 3271 (NH), 3032 (Ar—H), 1688 (C═O), 1610, 1515, 1412 (C═C). 1H NMR (500 MHz, CDCl3) δ=1.71 (m, 2H, CH2); 1.85 (m, 2H, CH2); 2.75 (m, 1H, CH); 2.95 (m, 2H, CH2); 3.32 (m, 2H, CH2); 5.23 (s, 2H, CH2); 6.82 (d, 1H, J=8.2 Hz, aromatic H); 7.02 (s, 1H, aromatic H); 7.09 (d, 1H, J=8.1 Hz, aromatic H); 8.61 (br. s, 1H, NH); 8.87 (br. s, 1H, NH); 10.11 (s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=29.51 (CH2), 38.34 (CH), 43.54 (CH2), 67.61 (CH2), 113.81 (aromatic-C), 118.68 (aromatic-C), 122.45 (aromatic-C), 126.84 (aromatic-C), 134.96 (aromatic-C), 138.77 (aromatic-C), 151.86 (C═O). Calculated (%) for C15H17F3N3O2 (328.13); C: 52.17, H: 5.25, N: 12.17. found (%); C: 52.08, H: 5.33, N: 12.07.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][C:19](O)=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O.Cl>C(Cl)(Cl)Cl.N1CCCCC1.C(N(CC)CC)C.C1(C)C=CC=CC=1.CC(C)=O.C(OCC)C>[ClH:24].[C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([N:8]3[CH2:9][CH2:14][CH2:15][CH2:16][CH2:7]3)=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)COc1cc(-c2ccccc2)nc2ccccc12
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: C1CCNCC1
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(COc1cc(-c2ccccc2)nc2ccccc12)N1CCCCC1

Procedure:
The procedure is as in Example 1, but starting with (2-phenyl-4-quinolyl)oxyacetic acid (3 g), thionyl chloride (2.35 cc) in chloroform (50 cc), piperidine (1.04 cc) and triethylamine (3 cc) in toluene (50 cc). The residue obtained is converted in acetone to its hydrochloride by adding a solution of hydrochloric acid in ethyl ether. After recrystallization in ethanol, 1-[(2-phenyl-4-quinolyl)oxyacetyl]piperidine hydrochloride (0.46 g), m.p. 146° C., is obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:31](=O)[CH2:32][CH2:33][CH3:34].C([BH3-])#N.[Na+]>CO>[CH2:31]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:30])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH2:32][CH2:33][CH3:34]
Reactant: NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Reactant: CCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 159 from (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone-hydrochloride, butyraldehyde and sodium cyanoborohydride in methanol.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].N(OC(C)(C)C)=O.[Cl:25]CCCl>ClCCl.[Cu](Cl)Cl>[Cl:25][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1N
Reactant: ClCCCl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2ccccn2)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 5-amino-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate (200 mg, 0.861 mmol) and copper (II) chloride (116 mg, 0.861 mmol) in 1,2-dichloroethane (8 mL) was added tert-butyl nitrite (0.154 mL, 1.292 mmol). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was diluted with 30 mL of dichloromethane and was washed with 10 mL of 2M NH4OH solution, 10 mL of brine and dried over Na2SO4. Filtration and concentration yielded a crude product which was purified on silica gel column eluting with hexanes/EtOAc to afford ethyl 5-chloro-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[C@H:10]([CH2:13][CH2:14][NH2:15])[CH2:11][O:12][C:8]=2[CH:7]=1.[C:23](Cl)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[C@H:10]([CH2:13][CH2:14][NH:15][C:23](=[O:25])[CH3:24])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: NCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)NCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reaction time: 2 h
Yield: 47.3 %

Procedure:
To a mixture of 2-((3S)-6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)ethanamine (320 mg) and DMA (10 mL) was added acetyl chloride (74.3 mg). The mixture was stirred for 2 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (170 mg).
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:7]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[C:11]3=[O:22])=[N:8][C:4]=2[CH:3]=1.[C:30](=[NH:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30](=[N:43][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:7]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[C:11]3=[O:22])=[N:8][C:4]=2[CH:3]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(Br)ccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Yield: 86.4 %

Procedure:
A mixture of 1-[5-bromo-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (45 mg, 0.1 mmol), benzophenone imine (22 mg, 0.12 mmol), sodium tert-butoxide (13 mg, 0.14 mmol), BINAP (19 mg, 0.03 mmol) and Pd2(dba)3 (9 mg, 0.01 mmol) in toluene (2 mL) was heated to reflux for 6 h. After cooling, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified by flash chromatography (hexanes:EtOAc 4:1 to 1:1) to give 48 mg (87%) of 1-[5-(benzhydrylidene-amino)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C@@H:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:18].Cl.[CH2:20](O)[CH3:21]>>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH2:12][C@@H:13]([OH:17])[C:14]([O:16][CH2:20][CH3:21])=[O:15])=[CH:4][C:3]=1[Cl:18]
Reactant: CCO
Reactant: Nc1c(Cl)cc(C[C@@H](O)C(=O)O)cc1C(F)(F)F
Agent: Cl
Product: CCOC(=O)[C@H](O)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A mixture of 14.3 g (50.0 mmol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-propionic acid and 100 ml of ethanol was combined with 100 ml of an approx. 12-molar ethanolic hydrochloric acid solution and stirred overnight. The reaction mixture was evaporated down under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1([CH2:6][CH:7]([C:14]([O:16]C(C)C)=[O:15])[C:8]([O:10]C(C)C)=[O:9])[CH2:5][CH2:4]1.[OH-].[Na+]>CO.O1CCOCC1.O>[F:1][C:2]([F:20])([F:21])[C:3]1([CH2:6][CH:7]([C:14]([OH:16])=[O:15])[C:8]([OH:10])=[O:9])[CH2:5][CH2:4]1
Reactant: CC(C)OC(=O)C(CC1(C(F)(F)F)CC1)C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)C(CC1(C(F)(F)F)CC1)C(=O)O
Temperature: 40 °C
Yield: 101.4 %

Procedure:
A solution of diisopropyl 2-((1-(trifluoromethyl)cyclopropyl)methyl)malonate (1.53 g, 4.93 mmol) in MeOH (10 mL), dioxane (10 mL) and H2O (10 mL) was treated with NaOH (1.183 g, 29.6 mmol) and heated at 40° C. overnight. The mixture was cooled to RT, the organics removed under reduced pressure, the aqueous residue acidified with 3M HCl, extracted with DCM and the combined organics were dried over Na2SO4 and concentrated to dryness to afford 2-((1-(trifluoromethyl)cyclopropyl)methyl)malonic acid (1.13 g, 101%). 1H NMR (400 MHz, DMSO-d6): δ 12.91 (s, 2H), 3.36-3.34 (t, J=7.09 Hz, 1H), 2.08 (d, J=7.0 Hz, 2H), 0.88 (m, 2H), 0.77 (m, 2H).
Reaction SMILES: CN1CCN(C)C1[C:8]1[S:9]C=[CH:11][CH:12]=1.CN(C)CCN(C)C.C([Li])CCC.ICC.[O:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:12]([C:8]1[S:9][C:31]([CH:30]=[O:29])=[CH:32][CH:33]=1)[CH3:11]
Reactant: C1CCOC1
Reactant: CN1CCN(C)C1c1cccs1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCI
Product: CCc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1,3-Dimethyl-2-(2-thienyl)imidazolidine (5.46 g) (synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) and N,N,N',N'-tetramethylethylenediamine (4.7 ml) were dissolved in tetrahydrofuran (150 ml). The mixture was cooled to -78° C., and n-butyllithium (1.6M in hexane, 19.5 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours, and iodoethane (2.4 ml) was added. The mixture was slowly heated to room temperature and then stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and 10% sulfuric acid (200 ml) was added to the residue. The mixture was stirred for 24 hours and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-ethyl-2-thiophenecarbaldehyde (1.68 g) as oil. 5-ethyl-2-thiophenecarbaldehyde (1.68 g) was dissolved in acetonitrile (20 ml), and sodium dihydrogen phosphate (0.54 g) in water (10 ml) and 30% hydrogen peroxide (2.0 ml) were added. Sodium chlorite (3.0 g) in water (20 ml) was then added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-ethyl-2-thiophenecarboxylic acid (1.48 g) as crystals.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:41])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:40])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:39])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:38])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])=[CH:3][C:4]#[N:5].[Na].Cl>CO.C1COCC1>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:41])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:40])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:39])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:38])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:37])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH2:3][C:4]#[N:5]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC#N
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
21 g of 3,7,11,15,19,23,27,31-octamethyl-2,6,10, 14,18,22,26,30-dotriacontaoctaenonitrile was dissolved in 250 ml of methanol and 100 ml of THF, and 24 g of metallic sodium was added. The reaction solution was stirred at room temperature for 30 minutes and was cooled with ice when foaming and heat generation were recognized. After the reaction solution was reacted for 2 hours, 500 ml of 6N hydrochloric acid was added and the reaction product was extracted by 500 ml of n-hexane. The organic layer was concentrated and the concentrate was refined by silica gel column chromatography, providing 16 g of 3,7,11,15,19,23,27,31-octamethyl-6,10, 14,18,22,26,30-dotriacontaheptaenonitrile.
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C1CCCCC1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15]/[C:2](/[CH2:8][CH3:9])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[CH:13][CH:12]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC/C(=C/C(=O)OC)Nc1ccc(F)cc1
Yield: 66.5 %

Procedure:
A mixture of methyl 3-oxovalerate (10.0 g, 76.8 mmol), 4-fluoroaniline (7.36 mL, 76.8 mmol), p-toluenesulfonic acid monohydrate (730 mg, 3.84 mmol), cyclohexane (40 mL) and toluene (10 mL) was stirred with heating under reflux for 15 hr. The mixture was concentrated under reduced pressure, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=99:1→92:8) to give the title compound (11.4 g, 67%) as a yellow oil.
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]1([CH3:42])[CH:27]=[CH:26][C:25]([C:28]#[C:29][P:30](=[O:41])([O:34][C:35]([CH2:37][CH2:38][CH2:39][Cl:40])=[CH2:36])[O:31][CH2:32][CH3:33])=[CH:24][CH:23]=1>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:41])[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:42])=[CH:23][CH:24]=2)[CH:36]=[C:35]([CH2:37][CH2:38][CH2:39][Cl:40])[O:34]1)[CH3:33]
Reactant: C=C(CCCCl)OP(=O)(C#Cc1ccc(C)cc1)OCC
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccc(C)cc2)C=C(CCCCl)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
Method 1—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tent-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl 5-chloropent-1-en-2-yl p-tolylethynylphosphonate (Example 9, 97.8 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-p-tolyl-6-chloropropyl-1,2-oxaphosphorin 2-oxide (76.3 mg, 78%) which is a title compound.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1.Br[C:20]1[CH:21]=[CH:22][C:23]2[N:29]([CH3:30])[CH2:28][CH2:27][C:26]([C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:48])[CH:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:36][CH:35]=3)=[O:32])=[CH:25][C:24]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH3:30])[CH2:28][CH2:27][C:26]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH2:40][N:41]([CH3:48])[CH:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[CH:38][CH:39]=4)=[O:32])=[CH:25][C:24]=3[CH:49]=2)=[CH:4][CH:5]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
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: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-(2-butoxyethoxy)phenyl borate (324 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (440 mg). To the solution was added potassium carbonate (301 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (42 mg), and the mixture was refluxed under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30 g, ethyl acetate→ethyl acetate:ethanol=10:1→ethyl acetate:ethanol:triethylamine=100:10:0.5) and recrystallized from ethyl acetate/IPE to give 7-[4-(2-butoxyethoxy)phenyl]-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 18) (287 mg, 53%) as yellow crystals.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[OH:12].[CH2:13]=[C:14]1[O:18][C:16](=[O:17])[CH2:15]1>C(O)C>[CH3:1][N:2]([C@@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@H:4]1[OH:12])[C:16](=[O:17])[CH2:15][C:14]([CH3:13])=[O:18]
Reactant: CN[C@@H]1Cc2ccccc2[C@H]1O
Reactant: C=C1CC(=O)O1
Solvent: CCO
Product: CC(=O)CC(=O)N(C)[C@@H]1Cc2ccccc2[C@H]1O
Reaction time: 1 h

Procedure:
To a solution of trans-2-methylamino-1-indanol (4.9 g, 0.03 m) in 100 ml of ethanol was added 2.8 g (0.033 m) of diketene. After stirring about 1 hour the mixture was concentrated to dryness in vacuo. The residue was dissolved in acetonitrile and the solvent was evaporated in vacuo to 6.3 g (85%) of an oily residue which was used directly in the next step.
Reaction SMILES: CS([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:6]1)(=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:29][C:25]1[CH:24]=[C:23]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[CH:9]=3)[NH:5][CH:6]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)n1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1ccc2[nH]cc(-c3cccc(Cl)c3)c2c1

Procedure:
To a solution of 1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole (11.44 g, 25.76 mrnmol, see Preparation 7) in anhydrous THF (150 ml) was added tetrabutylammonium fluoride (33.5 ml, 1.0 M solution in THF). The resulting solution was refluxed under nitrogen for about 3 hrs. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with 1N HCl (2 times), saturated NaHCO3 aqueous solution (2 times) and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with EtOAclhexane 1:4. The title compound was obtained as a yellow solid. Yield=8.1 g, 86%.