Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[NH2:30][CH2:31][CH2:32][C@H:33]1[O:38][B:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]1.C(O)(=O)C(C)(C)C>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]([CH2:31][CH2:32][C@H:33]3[O:38][B:37]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C@@H:35]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:34]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OB(c2ccccc2)O1
Agent: CC(C)(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OB(c2ccccc2)O1
Temperature: 22.5 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
To a nitrogen-filled flask, 126 g of 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione, 2.5 L of toluene, 41 ml of triethylamine, 160 g of t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-phenyl-1,3,2-dioxaborinan-4-yl)acetate and 33 ml of pivalic acid were added. The mixture was heated to reflux with stirring for 14 hours while removing water with a Dean-Stark trap. The reaction mixture was cooled slowly to 20-25° C. and washed with purified water, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, thus obtaining 194 g of the title compound as yellow oil.
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].S(O)(O)(=O)=O.[CH3:18][NH:19][NH2:20]>>[CH3:18][N:19]1[C:4]([C:5]([F:8])([F:7])[F:6])=[CH:3][C:2]([NH2:1])=[N:20]1
Reactant: CNN
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: Cn1nc(N)cc1C(F)(F)F
Yield: 23.1 %

Procedure:
Using the procedure described in Example 161A Step 3, (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (1.83 g, 10 mmol) and methylhydrazine sulfate (1.586 g, 11 mmol) were reacted and the crude product purified by silica gel chromatography (with 0-10% EtOAc/CH2Cl2 as eluants) to afford 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine as solid (0.381 g, 23%). 1H NMR (300 MHz, CDCl3) δ 5.94 (s, 1H), 3.78 (s, 3H), 3.67 (br, 2H); LC-MS (ESI) m/z 166 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[CH:30]=[C:18]2[N:19]=[C:20]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=[C:22]([NH2:23])[N:17]2[N:16]=1.CCN(CC)CC>CC#N>[CH3:9][C:4]1[C:3]([CH2:2][N:27]2[CH2:26][CH2:25][N:24]([C:20]3[N:21]=[C:22]([NH2:23])[N:17]4[N:16]=[C:15]([C:11]5[O:10][CH:14]=[CH:13][CH:12]=5)[CH:30]=[C:18]4[N:19]=3)[CH2:29][CH2:28]2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Nc1nc(N2CCNCC2)nc2cc(-c3ccco3)nn12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1CN1CCN(c2nc(N)n3nc(-c4ccco4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Chloromethyl-3,5-dimethyl-isoxazole (1.5 eq.) was directly added to a solution of 7-furan-2-yl-2-piperazin-1-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1 H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1 H), 6.2 (s, 1H) 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 1.6 (br s, 6H). MS: m/z: 395 [M+H]+.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([CH2:22][C:23](=O)[CH3:24])[CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH3:15])[CH3:10].[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])#[N:27].C([O-])(=O)C.[NH4+]>O.C(O)(=O)C>[C:26]([CH:28]([CH:23]([CH3:24])[CH2:22][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:15])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:29]([O:31][CH2:32][CH3:33])=[O:30])#[N:27]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)C(C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
In 200 ml. of benzene was dissolved 50 g. of farnesyl acetone, and then 28 g. of ethyl cyanoacetate, 5 g. of ammonium acetate and 5 g. of acetic acid were added to the solution. The mixture was then refluxed for 8 hours with removal of the produced water. The reaction mixture then was washed with water and dried. To this mixture there was added dropwise a solution of 4.3 g. of sodium borohydride in 50 ml. of ethanol, under stirring and at 10°-20° C. The stirring was continued for 1 hour. Then, 50 ml. of 10% acetic acid was added to the reaction mixture, and the mixture was subsequently washed with water and dried. The solvent was removed by evaporation and then the residue was purified by silica gel column chromatography to obtain 50.5 g. of the desired oily product.
Reaction SMILES: O[CH:2]([CH2:12][O:13][CH3:14])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10].CCN(S(F)(F)[F:21])CC.C(O)C>O1CCOCC1>[F:21][CH:2]([CH2:12][O:13][CH3:14])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[N+:9]([O-:11])=[O:10]
Reactant: COCC(O)Cn1ccnc1[N+](=O)[O-]
Reactant: CCN(CC)S(F)(F)F
Solvent: C1COCCO1
Solvent: CCO
Product: COCC(F)Cn1ccnc1[N+](=O)[O-]
Yield: 52 %

Procedure:
To a solution of 914 mg (4.54 mmol) of 1-(2'-hydroxy-3'-methoxypropyl)-2-nitroimidazole in 5.0 ml of dry dioxane, 1.00 g (6.20 mmol) of DAST was dropwise added with cooling by ice and then reacted for 2 hours at room temperature with stirring. After reaction, to the solution, 5.0 ml of ethanol was added to decompose excess DAST. The solution was then concentrated and subjected to isolation and purification by silica gel column chromatography to give 480 mg of 1-(2-'-fluoro-3'-methoxypropyl)-2-nitroimidazole.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7]([NH2:15])[C:8]2[S:13][CH:12]=[C:11]([CH3:14])[C:9]=2[N:10]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C.CCCCCC>ClCCl>[CH2:1]([NH:4][C:5]1[N:6]=[C:7]([NH:15][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]2[S:13][CH:12]=[C:11]([CH3:14])[C:9]=2[N:10]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C=CCNc1nc(N)c2scc(C)c2n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: C=CCNc1nc(NC(=O)C(C)(C)C)c2scc(C)c2n1
Yield: 43.5 %

Procedure:
To a solution of 150 mg (0.68 mmol) of 2-allylamino-4-amino-7-methylthieno[3,2-d]pyrimidine and 83 mg (0.82 mmol) of triethylamine in dichloromethane was added 82 mg (0.68 mmol) of pivaloyl chloride, followed by heating under reflux for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/4] to give 90 mg (yield: 43.5%) of the title compound.
Reaction SMILES: FC1C(F)=CC(F)=C(F)C=1CC(O)=O.[NH2:15]C1C(F)=C(F)C(CC(O)=O)=C(F)C=1F.N.[NH2-].[Na+].[F:33][C:34]1[C:47]([F:48])=[C:46](F)[C:45]([F:50])=[C:44]([F:51])[C:35]=1[C:36]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:37]>>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][C:36](=[O:37])[C:35]1[C:34]([F:33])=[C:47]([F:48])[C:46]([NH2:15])=[C:45]([F:50])[C:44]=1[F:51])[CH3:43]
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1c(F)c(F)c(CC(=O)O)c(F)c1F
Agent: N
Agent: O=C(O)Cc1c(F)c(F)cc(F)c1F
Agent: [NH2-]
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(N)c(F)c1F

Procedure:
The [4-amino(mono- or poly-fluoro)phenyl]alkanoic acids and esters required as intermediates are prepared by a sequence of reactions involving nitration of a suitable phenylalkanoic acid followed by reduction of the nitro group. For example, 2,3,5,6-tetrafluorophenylacetic acid is converted to 4-amino-2,3,5,6-tetrafluorophenylacetic acid by this method. The [4-amino-(mono- or poly-fluoro)benzoyl]alkanoic acids and esters are prepared by the reaction of ammonia or sodium amide with (4-halobenzoyl)alkanoic acids. For example, the reaction of sodium amide with ethyl 2,3,4,5,6-pentafluorobenzoylacetate yields ethyl(4-amino-2,3,5,6-tetrafluorobenzoyl)acetate.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[S:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1>O1CCOCC1.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>[CH:1]([C:17]1[S:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1)=[CH2:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ncc(C(=O)OCC)s1
Temperature: 100 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution of tributyl(vinyl)stannane (0.92 mL, 3.14 mmol) and ethyl 2-bromothiazole-5-carboxylate (0.38 mL, 2.54 mmol) in dioxane (33 mL) is added Pd(PPh3)2Cl2 (182 mg, 0.26 mmol) at room temperature. After stirring at 100° C. under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with H2O. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=90:10 to 80:20) to give ethyl 2-vinylthiazole-5-carboxylate (418 mg). HPLC retention time=0.45 minutes (condition B); MS (m+1)=184.1; 1H NMR (400 MHz, CD3OD) δ ppm 1.37 (t, J=7.2 Hz, 3H) 4.35 (q, J=7.1 Hz, 2H) 5.71 (d, J=10.9 Hz, 1H) 6.24 (d, J=17.4 Hz, 1H) 6.93 (dd, J=17.4, 10.9 Hz, 1H) 8.29 (s, 1H)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][C@H:4]1[F:20].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C([O-])(O)=O.[Na+]>C(O)CCC.C(N(C(C)C)CC)(C)C.CCOC(C)=O>[F:20][C@H:4]1[C@@H:3]([CH2:2][NH:1][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[O:10])[CH2:5]1
Reactant: Cc1ccc(COC(=O)N2CC[C@H](CN)[C@H](F)C2)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc(COC(=O)N2CC[C@H](CNc3ncccn3)[C@H](F)C2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 145.8 %

Procedure:
Two sealed tubes were each charged with a mixture of crude (±)-cis-4-methylbenzyl 4-(aminomethyl)-3-fluoropiperidine-1-carboxylate (Step 6, 3.7 g, 13.2 mmol) and 2-chloropyrimidine (1.51 g, 13.2 mmol) in n-butanol/diisopropyl-ethylamine (1:1, 13 mL). The tubes were sealed and the mixtures heated to 140° C. and stirred for 2 h. After cooling to RT, the reaction mixtures were combined and diluted with EtOAc and sat NaHCO3. The layers were separated and the organic was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc) gave racemic cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate (6.9 g, 65% yield, 3 steps) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[I:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.O>CN(C=O)C>[I:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccc(Cn2ccnc2)cc1
Reaction time: 11.5 h
Yield: 45.2 %

Procedure:
To a solution of imidazole (400 mg, 5.88 mmol) and K2CO3 (1.22 g, 8.81 mmol) in DMF (19 ml) was added 4-iodobenzyl bromide (1.83 g, 6.17 mol) at RT under protection from light. After stirring for 11.5 h, the reaction mixture was poured into water. The aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford the title compound (757 mg, 2.66 mmol, 45%) as a beige solid. HPLC: EtRet=3.838 min; LC-MS: m/z 285.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH2:22][C@H:21]([CH3:25])[N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>>[Cl:34][C:16]1[CH:15]=[C:14]([CH:12]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([CH3:11])=[N:9]2)[CH3:13])[C:24]2[O:23][CH2:22][C@H:21]([CH3:25])[N:20]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:19][C:18]=2[C:17]=1[F:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OC[C@H](C)N(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OC[C@H](C)N(S(C)(=O)=O)C3)c2ncnc(N)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-3-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (13 mg, 0.026 mmol) was stirred in methylene chloride (100 μL, 2 mmol) with N,N-diisopropylethylamine (14 μL, 0.079 mmol) and cooled to 0° C. Methanesulfonyl chloride (2.6 μL, 0.034 mmol) was added, and the mixture was stirred at 0° C. for 1 hr. The mixture was evaporated and diluted with methanol. The reactions were purified by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two enantiomers: Peak #1 (Example 35): LCMS calculated for C19H23ClFN6O3S (M+H)+: m/z=469.1; found: 469.1; Peak #2 (Example 36): LCMS calculated for C19H23ClFN6O3S (M+H)+: m/z=469.1; found: 469.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:14]([CH2:28][CH2:29][CH3:30])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25](I)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:12][CH3:13]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:28]([N:14]([CH2:11][CH2:12][CH3:13])[C:15]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:16])[CH2:29][CH3:30]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-iodobenzoic acid (12 g, 32 mmol) is dissolved in 20% methanol/benzene (480 mL), and 2M trimethylsilyldiazomethane in hexane (19 mL, 38 mmol) is added slowly. Upon completion of the addition, the solution is concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate for use without further purification in the following reaction. To a −70° C. stirred solution of oxazole (120 mg, 1.7 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.2 mL, 1.9 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 5.2 mL, 5.2 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (643 mg, 1.6 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0)tetrakis(triphenylphosphine) (80 mg, 0.07 mmol). The reaction mixture is heated at reflux for 3 h. The reaction mixture is cooled, diluted with ethyl acetate, filtered, washed with saturated sodium bicarbonate, water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound in pure form. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H) 7.32 (s, 1H), 3.52 (t, 2H), 3.22 (t, 2H), 1.75 (m, 2H), 1.30 (m, 2H), 0.97 (t, 3H), 0.79 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[C:15]2[C:6]([C:7](=[O:18])[C:8]3[C:13]([C:14]2=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:5]2[CH2:19][CH2:20][CH2:21][C:4]=12.[C:22]([O-:25])(=[O:24])[CH3:23].[K+]>CN(C)C=O.ClCCl>[C:22]([O:25][CH2:2][C:3]1[CH:16]=[C:15]2[C:6]([C:7](=[O:18])[C:8]3[C:13]([C:14]2=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:5]2[CH2:19][CH2:20][CH2:21][C:4]=12)(=[O:24])[CH3:23]
Reactant: O=C1c2ccccc2C(=O)c2c1cc(CBr)c1c2CCC1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc2c(c3c1CCC3)C(=O)c1ccccc1C2=O
Reaction time: 2.5 h

Procedure:
To a solution of 2,3-dihydro-4-bromomethyl-1H-cyclopent[a]-anthracene-6,11-dione (173 mg, 0.51 mmol) in dimethylformamide (10 ml) is added anhydrous potassium acetate (200 mg) at 0° C. and stirred for 2.5 hours. The mixture is diluted with dichloromethane (50mL), washed with H2O, dried (Na2SO4), and evaporated in vacuo to dryness. The residue is chromatographed on a silica gel column (2×30 cm) using toluene/ethyl acetate (9:1 v/v) as the eluent. The main fraction is collected, evaporated, and the solid residue is recrystallized from EtOH to afford 4-acetoxymethyl-2,3-dihydro-1H-cyclopent[a]anthracene-6,11dione, 81 mg (50%), mp 160°-161° C. 1H NMR (CDCl3): δ2.18 (3H, s, Ac), 2.24 (2H, t, J=7.6 Hz, CH2 -2), 2.98 (2H, q, J=7.6 Hz, CH2 -3), 3.53 (2H, t, J=7.6 Hz, CH2 -1), 5.20 (2H, S, CH2 --OAc), 7.76-8.30 (5H, m, Ar--H). The product is used directly in the next step without further purification.
Reaction SMILES: C(#N)C.[CH3:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[CH2:6]([N:5]([CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])[CH3:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)C(=O)OC
Reactant: CNCc1ccccc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To an acetonitrile (60 mL) solution of N-methylbenzylamine (15 mL), an acetonitrile (10 mL) solution of dimethyl bromomalonate (12 g) was added dropwise at room temperature, and the mixture was stirred for 6 hours at room temperature. Toluene (0.20 L) was added, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. To the residue, toluene (0.10 L) and OH type silica gel (6.0 g) were added, and the mixture was stirred for 20 minutes at room temperature and then filtered. The filtrate was concentrated under reduced pressure to obtain dimethyl [benzyl(methyl)amino]propanedioate (pale yellow oil) (14 g, 96%).
Reaction SMILES: C[O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:20](=[CH:21][CH:22]=1)[O:19][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:23].Cl>CC(O)=O>[CH3:18][N:14]1[CH2:15][CH2:16][CH2:17][C:11]2([CH2:10][C:9](=[O:23])[C:8]3[C:20](=[CH:21][CH:22]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:24])=[O:2])[CH:7]=3)[O:19]2)[CH2:12][CH2:13]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C)CC1)O2
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Yield: 94.6 %

Procedure:
(±)-(E)-3-[1′-Methyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (370 mg, 1.12 mmol) was hydrolyzed with HCl and AcOH according to the procedure for preparation of Example 23, Step B, giving (±)-(E)-3-[1′-methyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid (334 mg) as a white solid (hydrochloride salt).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[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)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][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:29])[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]([CH2:31][C:32]5[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=5[CH3:34])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[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]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: Cc1ccccc1C[Zn+]
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccccc3C)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-benzylzinc chloride 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 6): tR=1.29 min; Mass spectrum (ESI+): m/z=497 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.[BH4-].[Na+].[C:31](O)(=O)[CH3:32]>>[CH2:31]([N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[C:25]([F:28])([F:26])[F:27])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3)[CH3:32]
Reactant: CC(=O)O
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3
Temperature: 55 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
To a solution of (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) in acetic acid (0.28 mL) was added NaBH4 (30 mg, 0.80 mmol) in 2 portion in 10 min interval at 55° C. The reaction mixture was stirred for 15 h at 55° C. then quenched by addition of H2O. The aqueous solution was basified with 50% NaOH then extracted with CHCl3. The combined organic solution was dried over MgSO4, concentrated in vacuo. The residue was chromatographed (silica gel; CHCl3:MeOH 99:1-98:2) to give the title compound as a yellow oil (26 mg, 81%). 1H NMR (CDCl3, 300 MHz) δ1.21-1.35 (m, 3H), 2.05-2.30 (m, 5H), 2.53-2.78 (m, 6H), 2.98-3.07 (br, 1H), 3.08-3.18 (br, 1H), 3.27-3.42 (m, 2H), 3.43-3.57 (br, 1H), 3.88 (s, 3H), 6.83 (s, 1H), 6.86 (s, 1H), 7.04 (dd, J=8.8, 2.9 Hz, 1H), 7.20-7.26 (m, 2H) ppm. MS (CI, NH3): 417.1 (base, M+H).