Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH:6]=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:4]=1)[CH3:2].CCCCCC.C([Li])CCC.[C:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C)P(=O)(N(C)C)N(C)C.C1COCC1>[C:8]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:7](=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCC1=CC(C(C)(C)C)=CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 53.1 %

Procedure:
To a 200 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 3.16 g (21.2 mmom) of 1-ethyl-3-tert-butyl-cyclopentadiene and 100 ml of THF were charged under a nitrogen atmosphere. In the ice/methanol bath, 14 ml (22 mmol) of 1.58M n-butyllithium hexane solution was added dropwise over 45 minutes and stirred for 4 hours. Thereto, 8 ml of hexamethylphosphoric triamide, subsequently 5.85 g (32.1 mmol) of benzophenone were charged, and the solution was stirred for 27 hours at room temperature. The reaction solution was poured into 400 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with 150 ml of ether. The obtained organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated aqueous solution of sodium chloride, and dried over magnesium sulfate and the solvent was distilled off, and purified by column chromatography to obtain 3.51 g of an orange solid. The yield was 53%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](N)[S:8][C:4]=2[CH:3]=1.C([CH2:14][O:15][C:16]1[C:17]([F:26])=[C:18]([C:23]([NH2:25])=[O:24])[C:19]([F:22])=[CH:20][CH:21]=1)#N>>[F:26][C:17]1[C:16]([O:15][CH2:14][C:7]2[S:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=3[N:6]=2)=[CH:21][CH:20]=[C:19]([F:22])[C:18]=1[C:23]([NH2:25])=[O:24]
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Product: Cc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2c1
Yield: 17 %

Procedure:
Synthesised from 6-methyl-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzene carboxamide, according to Method K, scheme 26. Yield 17% (second step), HPLC-MS (method 1): m/z 335 [M+H]+, Rt=3.70 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][NH2:19])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH2:18][CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: NCCc1cccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCc2cccnc2)cc1
Temperature: 60 °C
Yield: 92.8 %

Procedure:
2 g of 4-fluoronitrobenzene, 2.07 g of 2-(3-pyridyl)ethylamine, and 2.35 g of K2CO3 were added to a solution of 20 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 16 hours and, after cooling to room temperature, was then poured into a water+ice mixture. The yellow precipitate formed was filtered off, reslurried in water, and then dried over P2O5. 3.2 g of N-(4-nitrophenyl)-N-(2-pyrid-3-ylethyl)amine (3) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:23])[CH2:14][CH2:13][S:12][C:11]([NH:15]C(=O)OC(C)(C)C)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:23])[CH2:14][CH2:13][S:12][C:11]([NH2:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2ccc(F)c(Br)c2)CCS1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@@]1(c2ccc(F)c(Br)c2)CCSC(N)=N1
Temperature: 60 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-bromo-4-fluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-ylcarbamate (1.1 g, 2.7 mmoles) and methanol (10 mL) is added trifluoroacetic acid (10 mL). The reaction mixture is warmed to 60° C. After 15 h, the solvent is removed under reduced pressure. Water is added to the resulting residue and the mixture is made basic with saturated sodium bicarbonate. The basic aqueous phase is extracted with dichloromethane. The organic phase is separated, dried over sodium sulfate, filtered, and the solvent removed under reduced pressure to give the title compound (62% yield): MS (m/z): 303, 305 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=2)[N:3]=[CH:2]1.[Li]>C1COCC1>[NH:1]1[CH:5]=[C:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[N:3]=[CH:2]1
Reactant: CCOC(=O)c1csc(-c2c[nH]cn2)n1
Agent: [Li]
Solvent: C1CCOC1
Product: O=C(O)c1csc(-c2c[nH]cn2)n1
Reaction time: 4 h

Procedure:
Ethyl 2-(1H-imidazol-4-yl)thiazole-4-carboxylate (1.5 g, 6.72 mmol) was dissolved in THF (10 ml). Into the suspension, lithium hydroxyde monohydrate 1M solution (13.44 ml, 13.44 mmol) was added and the resulting mixture was stirred for 4 h. Then 3.36 ml of lithium hydroxyde monohydrate 1M solution was added and the mixture was stirred for another hour. The mixture was evaporated, 10 ml of water added and the pH was adjusted to 1 with concentrated HCl. The precipitate was filtered. Both the filtrate and filtered precipitate contained the product. The filtrate was dissolved in toluene and evaporated twice. LC-MS: [M+1]=196.20.
Reaction SMILES: [C:1]([C:3]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[F:15])#[N:2].[OH-:16].[K+]>C(O)(C)(C)C>[CH3:14][C:10]1([CH3:13])[CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([F:15])=[C:3]([C:1]([NH2:2])=[O:16])[C:12]=2[O:11]1
Reactant: [OH-]
Reactant: CC1(C)C=Cc2ccc(F)c(C#N)c2O1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(C)C=Cc2ccc(F)c(C(N)=O)c2O1

Procedure:
Schema 6 illustrates the synthesis of an amino substituted 2,2-dialkyl-2H-1-benzopyran and an amino substituted 2,2-dialkyl-3,4-dihydro-2H-1-benzopyran, for example, 8-amino-5-chloro-7-fluoro-2H-1-benzopyran and 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran by the reaction of an appropriately substituted 2-fluorobenzonitrile with 2-methyl-3-butyn-2-ol under basic conditions in dimethyl sulfoxide, yielding the corresponding 3-(2-cyano-substituted-phenoxy)-3-methyl-1-butyne (XXI). The butyne intermediate is then cyclized at 180° C. in 1,2-dichlorobenzene, giving the appropriate 8-cyano-2,2-dialkyl-7-fluoro-2H-1-benzopyran, for example, 8-cyano-2,2-dimethyl-7-fluoro-2H-1-benzopyran (XXII), which is in turn treated with potassium hydroxide in t-butanol, yielding 2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-ylcarboxamide (XXIII). The so-prepared carboxamide is then reduced with sodium hypochlorite and sodium hydroxide in water and dioxane, affording the corresponding free amine, for example, 8-amino-2,2-dimethyl-7-fluoro-2H-1-benzopyran (XXIV). The intermediate benzopyran is optionally halogenated in the 5-position as described above, yielding the corresponding benzopyran intermediate, for example, 8-amino-5-chloro-2,2-dimethyl-7-fluoro-2H-1-benzopyran (XXV). To obtain an amino substituted 2,2-dialkyl-3,4-dihydro-2H-1-benzopyran, for example, 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran, the benzopyran (XXIV), described above, is first hydrogenated in the presence of 5% palladium on carbon in ethanol. The so-prepared 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran (XXVI) is then optionally halogenated in the 5-position, affording the desired 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran (XXVII). Examples 13 and 14 provide detailed descriptions of how these compounds are prepared.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN1CCCC1=O>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:6]5[S:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1ncsc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: Cc1ncsc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 79.1 %

Procedure:
Using 4-methyl-1,3-thiazole-5-carboxylic acid (143 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (179 mg, yield 79%) was obtained.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:12][CH2:13][O:14]C)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.C(=O)=O>C1COCC1.C(OCC)(=O)C>[C:1]([C:5]1[C:6]2[O:12][C:13](=[O:14])[CH2:11][C:7]=2[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1c(C)cccc1C(C)(C)C
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc2c1OC(=O)C2
Temperature: -30 °C
Yield: 37.2 %

Procedure:
A solution of 43 (3.0 g, 14.4 mmol) and TMEDA (2.6 ml, 17.3 mmol) in THF (40 ml) was cooled to −50° C., and dropwise and slowly added with sec-BuLi (1.3 M in cyclohexane, 13.3 ml, 17.3 mmol). The reaction mixture was warmed to −30° C., and then cooled again to −60° C., and dry ice was added to the mixture. The reaction mixture was warmed to room temperature over 1 hour, added with waster (50 ml) and ethyl acetate (50 ml). The aqueous layer was separated, acidified with 2N HCl to pH 3-4, and extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml), and dried. The solvent was removed in vacuo. The residue was dissolved in toluene (50 ml), added with p-TsOH.H2O (250 mg), and heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and poured into an aqueous diluted sodium bicarbonate solution (60 ml). The organic layer was separated and washed with saturated brine (60 ml). After drying, the solvent was removed in vacuo, and the residue was purified by column chromatography to yield 1.02 g (37%) of 44. 1H NMR (CDCl3) δ: 1.40 (9H, s, tBu), 3.71 (2H, s, CH2), 7.02-7.27 (3H, m, 3×Ar—H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH2:11][CH2:12][OH:13])[CH3:10]>O1CCCC1>[C:4]([O:13][CH2:12][CH2:11][N:9]([CH3:10])[CH3:8])(=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: CN(C)CCO
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: CN(C)CCOC(=O)CCC(=O)O
Reaction time: 2 h

Procedure:
In a two liter four neck flask equipped with stirrer, thermometer, condenser and addition funnel were charged succinic anhydride (200 g) and tetrahydrofuran (1400 ml). A homogeneous solution of succinic anhydride in tetrahydrofuran was made when the pot temperature reached 50° C. with external heating. Dimethylaminoethanol (178 g) was added at a rate that the exothermic reaction kept the pot temperature at 55° C. to 60° C. The reaction mixture was digested at 50° C. for a period of two hours after the addition of dimethylaminoethanol was completed. A first crop of crystalline product was collected by filtration and a second crop of product was collected from the mother liquor after concentration to 250 ml by means of reduced pressure distillation. These products were combined and dried in a vacuum over at 40° C. and 3 mm Hg pressure. The total yield was 303 g, 80% of the theoretical yield.
Reaction SMILES: [C:1]([C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][C@H:24]([CH2:26][OH:27])[O:23][C:22]4=[O:28])=[CH:17][C:16]=3[F:29])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O[C:31]1[CH:35]=[CH:34][O:33][N:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[C:1]([C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][C@H:24]([CH2:26][O:27][C:31]5[CH:35]=[CH:34][O:33][N:32]=5)[O:23][C:22]4=[O:28])=[CH:17][C:16]=3[F:29])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Oc1ccon1
Reactant: N#Cc1ccc(N2CCN(c3ccc(N4C[C@H](CO)OC4=O)cc3F)CC2)nn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc(N2CCN(c3ccc(N4C[C@H](COc5ccon5)OC4=O)cc3F)CC2)nn1
Yield: 25.8 %

Procedure:
3-(4-(4-(6-Cyano-3-pyridazinyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-hydroxy methyloxazolidin-2-one (398 mg, 1 mmol), 3-hydroxyisoxazole (93.5 mg, 1.1 mmol) and triphenylphosphine (328 mg, 1.25 mmol), were suspended with stirring in dry tetrahydrofiran (10 ml). Diisopropylazodicarboxylate (242 mg, 1.2 mmol) was added dropwise by syringe, and the mixture stirred at ambient temperature for 30 minutes. The reaction mixture was filtered, evaporated to dryness, dissolved in EtOAc/isohexane (1:1), and applied to a 10 g silica Mega Bond Elut® column, eluting with a gradient from 75 to 100% EtOAc in isohexane. Relevant fractions were combined and evaporated to give the title compound (120 mg).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:30][CH3:31])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC(F)F
Temperature: 70 °C
Yield: 23.2 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and ethyl iodide (153 mg, 0.98 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 23%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:29]=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10](=[O:12])[NH:27][C:28]1[CH:29]=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}propanoic acid LXXV (450 mg 1.21 mmol) and 3-aminoquinoline (187 mg, 1.30 mmol) in DCM (20 mL) was added DMT-MM (387 mg, 1.4 mmol). The mixture was stirred at r.t. overnight. The reaction was washed with water, 1 N HCl, satd. aq. NaHCO3, water and dried over Na2SO4. The product was purified on a silica gel column (1:1 EtOAc:hexane) to give tert-butyl 4-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-2-[(quinolin-3-yl)carbamoyl]ethyl]piperidine-1-carboxylate (425 mg, 0.85 mmol, 70% yield). 1H NMR (DMSO-d6) 1.02-1.10 (m, 2H), 1.40 (s, 18H), 1.54-1.73 (m, 9H), 4.22-4.25 (m, 1H), 7.20 (d, J=8 Hz, 1H), 7.55-7.66 (m, 2H), 7.94 (t, J=8 Hz, 2H), 8.69 (d, J=2 Hz, 1H), 8.93 (d, J=2 Hz, 1H), 10.44 (s, 1H). ESIMS found for C27H38N4O5 m/z 499 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]1([C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[C:19]([NH:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=2[CH3:29])=[O:20])[CH2:15][CH2:14]1)#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]1([C:16]2[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=2)[C:19]([NH:21][C:22]2[CH:27]=[C:26]([O:28][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)[CH:25]=[CH:24][C:23]=2[CH3:29])=[O:20])[CH2:15][CH2:14]1)#[N:12]
Reactant: Cc1ccc(O)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 103.6 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (3.25 g, 20.5 mmol) and 3-(1-cyanocyclopropyl)-N-(5-hydroxy-2-methylphenyl)benzamide (6.0 g, 20.5 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (7.08 g, 51.3 mmol), and the mixture was stirred at 60° C. for 12 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (300 mL), washed with water (300 mL), 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→30/70). The obtained solution was concentrated under reduced pressure to give the title compound (8.8 g, quantitative) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=4)[C:29]([C:38](=[O:51])[C:39]4[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=4)=[CH:28]3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:52])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=4)[C:29]([C:38](=[O:51])[C:39]4[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[C:41]([O:49][CH3:50])[CH:40]=4)=[CH:28]3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:13][O:12][C:11]([CH3:14])([CH3:15])[O:10][CH2:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Agent: [Pd]
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(CCC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Reaction time: 16 h

Procedure:
A mixture of the product of Step D (0.09 g, 0.12 mmol) and 10% Pd/C (0.04 g) was stirred for 16 h under H2 (balloon). The catalyst was removed by filtration through Celite pad, the filtrate evaporated to dryness, to give the product (0.065 g; 73%), as pale paste. 1H-NMR (CDCl3) 1.37 (s, 3H); 1.40 (s, 3H); 1.42 (s, 9H); 1.87-1.93 (m, 2H); 2.52-2.57 (m, 2H); 3.62 (d, 2H, J=11.77 Hz); 3.80 (d, 2H, J=11.55 Hz); 3.89 (s, 3H); 3.90 (s, 6H); 3.95 (s, 3H); 6.98 (dd, 1H, J=2.26, 8.80 Hz); 7.11 (s, 2H); 7.26 (d, 2H, J=8.37 Hz); 7.49 (d, 1H, J=2.16 Hz); 7.78 (d, 2H, J=8.37 Hz); 7.91 (s, 1H); 8.09 (d, 1H, J=8.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:32][C:31]5[CH:30]=[C:29]([F:28])[CH:36]=[C:35]([F:37])[CH:34]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: Fc1cc(F)cc(C[Zn+])c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5cc(F)cc(F)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3,5-difluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9): tR=0.91 min; Mass spectrum (ESI+): m/z=491 [M+Na]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=O)(C)(C)C>>[CH2:1]([N:8]1[C:12]2[C:13]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1Cn1c(=O)n(Cc2ccccc2)c2c(Cl)nccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: N#Cc1ccccc1Cn1c(=O)n(Cc2ccccc2)c2c(N3CCNCC3)nccc21

Procedure:
2-(3-benzyl-4-chloro-2-oxo-2,3-dihydroimidazo[4.5-c]pyridin-1-ylmethyl)benzonitrile (0.364 g) and piperazine-1-carboxylic acid t-butyl ester (0.543 g) were heated at 170° C. for 12 hours. The residue was cooled, and then purified by silica gel chromatography using amine-treated silica.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:23]1[CH:36]=[CH:35][C:34]2[C:25](=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH:24]1[C:25]2[C:34](=[CH:33][C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:35]=[CH:36][C:23]=1[C:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:18]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:9]=1
Reactant: OB(O)c1cc2ccc3ccccc3c2c2ccccc12
Reactant: Brc1ccc2cc3ccccc3cc2c1
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: [Na+]
Solvent: COCCOC
Product: c1ccc2cc3cc(-c4cc5ccc6ccccc6c5c5ccccc45)ccc3cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Under an argon atmosphere, 5.98 g of benzo[c]phenanthrene-5-boronic acid, 5.14 g of 2-bromoanthracene, 0.462 g of tetrakis(triphenylphosphine)palladium(0), 30 mL of 1,2-dimethoxyethane and 15 mL of a 2M aqueous solution of sodium carbonate was charged, and the mixture was refluxed with stirring for 8 hours. After cooling to room temperature, deposited crystals were separated by filtration. The resulting solids were recrystallized with toluene-hexane and washed repeatedly, whereby 6.07 g (yield: 75%) of 5-(2-anthryl)benzo[c]phenanthrene was obtained.