Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH:29]=[CH:30][CH:31]=[CH:32][C:33](Cl)=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:33](=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:23]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: Fc1ccc(CNCC=Cc2ccc(Cl)cc2)cc1F
Reactant: O=C(Cl)C=CC=Cc1ccc(Cl)cc1Cl
Product: O=C(C=CC=Cc1ccc(Cl)cc1Cl)N(CC=Cc1ccc(Cl)cc1)Cc1ccc(F)c(F)c1

Procedure:
The cis-diaryl compounds were prepared as shown above. To a solution of 4-chlorocinnamaldehyde (1.45 g, 8.70 mmol) in 100 mL of dichloroethane was added 3,4-difluorobenzylamine followed by sodium triacetoxyborohydride (3.7 g, 17.5 mmol, 2 eq.). The mixture was stirred overnight at room temperature, washed with aq. NaHCO3, brine, dried over MgSO4, filtered, concentrated and chromatographed with 40% ethyl acetate-hexanes to provide 0.84 g of [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amine. The [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amine was coupled with 5-(2,4-dichloro-phenyl)-penta-2,4-dienoyl chloride to provide 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amide. When 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amide was subjected to the Diels-Alder reaction conditions shown above, it gave 60 as the major product. Epimerization of the trans-lactam gave 61 and reduction of the double bond of 61 gave 62.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.Cl.[F:62][C@@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:65]3[CH2:66][CH2:67][C@@H:63]([F:62])[CH2:64]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 96.5 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.140 g, 0.54 mmol), triethylamine (0.4 mL, 2.6 mmol) and (R)-3-fluoropyrrolidine hydrochloride (68 mg, 0.54 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((R)-3-fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 25a (0.162 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([O:16][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (19.17 g, 51.35 mmol) in DMF (30 mL) was added potassium bicarbonate (6.16 g, 61.62 mmol) followed by benzyl bromide (6.2 mL, 51.41 mmol). The mixture was stirred for 5 h at room temperature and then water (150 mL) was added. The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (100 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the corresponding product (21.42 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.51 (dd, J=8.5, 2.1 Hz, 1H), 7.46-7.36 (m, 10H), 7.12-7.06 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.85 (m, 1H), 5.33 (s, 2H), 5.15 (s, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH3:26][Si:27](Cl)([CH3:29])[CH3:28]>ClCCl>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:27]([CH3:29])([CH3:28])[CH3:26])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: C[Si](C)(C)Cl
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1(CO[Si](C)(C)C)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene was dissolved in 20 ml of dichloromethane. The solution was cooled in ice-water bath to below 5° C., and 0.7 ml of triethyl amine was added thereto. After stirring for 5 minutes, 0.6 ml of trimethylsilyl chloride was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.41 g of concentrate (yield 86%). MS(EI) m/e: 312(M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[CH:4][N:3]=1.[F:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20]>>[F:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1)=[O:20]
Reactant: C[C@H]1COCCN1c1ccnc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1ccnc(-c2ccc(NC(=O)NCCF)cc2)n1

Procedure:
Method as described for example 49 using (S)-4-(2-chloropyrimidin-4-yl)-3-methylmorpholine (intermediate 3) and 1-(2-fluoroethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 19). The mixture was purified by prep HPLC at high pH to afford the title compound. (15 mg, 9%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:20]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]2)[CH:8]=[C:9]([N:12]([CH3:19])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]=1[CH3:11])=[O:4].[OH-].[Na+]>C1COCC1.CO>[C:27]([O:26][C:24]([N:22]1[CH2:23][CH:20]([C:7]2[CH:8]=[C:9]([N:12]([CH3:19])[CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:10]([CH3:11])=[C:5]([CH:6]=2)[C:3]([OH:4])=[O:2])[CH2:21]1)=[O:25])([CH3:29])([CH3:30])[CH3:28]
Reactant: COC(=O)c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(N(C)C2CCOCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)cc(C2CN(C(=O)OC(C)(C)C)C2)cc1N(C)C1CCOCC1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
To a dry flask was added zinc dust (436 mg, 6.67 mmol) and the flask was heated using a heat gun for a few minutes. Then anhydrous DMA (20 ml) was added under nitrogen whilst stirring vigorously and heating to 65° C. TMS-Cl (102 μl, 0.8 mmol) and 1,2-dibromoethane (70 μl, 0.8 mmol) were added and the reaction was stirred at 65° C. for 30 min followed by the dropwise addition of N-Boc-3-iodoazetidine (1.46 g, 5.16 mmol) as a solution in anhydrous DMA (15 ml). The reaction was then cooled to room temperature and methyl 5-bromo-2-methyl-3-[methyl(oxan-4-yl)amino]benzoate (1.06 g, 3.09 mmol) was added as a solution in anhydrous DMA (15 ml). The resulting solution was degassed with nitrogen for 10 mins after which Pd(dppf)Cl2.DCM (76 mg, 0.09 mmol) and copper (I) iodide (35 mg, 0.19 mmol) were added as solids. The reaction was heated to 80° C. for 90 min and then cooled to room temperature followed by the addition of distilled water (100 ml) and saturated NH4Cl solution (10 ml). The aqueous phase was extracted with TBME (3×50 ml), and then the combined organic phases were dried with Na2SO4, filtered and evaporated. The residue was purified over a 25 g Isolute column using 0%-40% EtOAc in heptane as the eluent to afford the title compound as a pale brown oil (507 mg). LC-MS 97%, m/z=420.0. To a stirred solution of tert-butyl 3-[3-(methoxycarbonyl)-4-methyl-5-[methyl(oxan-4-yl)amino]phenyl]azetidine-1-carboxylate (85 mg, 0.2 mmol) in THF (2 ml) and MeOH (0.1 ml) was added 2M NaOH solution (1.02 ml, 2.03 mmol) and the reaction was stirred at 50° C. for 16 h after which time 4M NaOH solution (0.5 ml, 2.0 mmol) was added and the reaction was heated for a further 24 h. The reaction was cooled to room temperature and the solvent removed in vacuo after which the aqueous solution was adjusted to pH3 using 1M HCl. The product was extracted into DCM (2×50 ml), washed with brine (20 ml), dried with Na2SO4 and filtered to afford the title compound as an off-white solid (47 mg, 21% over two steps). LC-MS 95%, m/z=405.1, 1H NMR (500 MHz, Chloroform-d) δ 7.66 (t, J=7.0 Hz, 1H), 7.19 (d, J=1.3 Hz, 1H), 4.34 (t, J=8.7 Hz, 2H), 3.98 (dd, J=16.6, 10.2 Hz, 4H), 3.79-3.69 (m, 2H), 3.35 (dd, J=11.5, 10.0 Hz, 2H), 2.97 (td, J=10.8, 5.3 Hz, 1H), 2.67 (s, 3H), 2.55 (d, J=6.6 Hz, 3H), 1.74 (ddd, J=15.5, 12.1, 4.3 Hz, 2H), 1.66 (d, J=11.1 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)#[N:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl>[CH2:14]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:3]([C:1]#[N:2])=[C:4]1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:21])=[CH:18][CH:17]=1)[CH3:15]
Reactant: C1COCCN1
Reactant: CCn1c(-c2ccc(C(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(C(=O)N3CCOCC3)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (50 mg, 0.16 mmol) is suspended in CH2Cl2 (2.2 mL) and catalytic DMF (2 μL). Oxalyl chloride (22 μL, 0.25 mmol) is added. The reaction mixture is stirred at room temperature for 1 hour, at which time full dissolution occurred. This reaction mixture is pipetted dropwise into a vigorously stirring solution of morpholine (1.0 mL) in CH2Cl2 (5 ml). After addition is complete, the reaction mixture is washed with aqueous HCl solution. The organic layer is dried and concentrated. Purification by silica column (1:1 CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 90%) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC#N.Cl[CH2:27][C:28]([N:30]1[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([CH2:27][C:28]([N:30]3[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]3)=[O:29])[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCNCC2)c1F
Reactant: COC1CN(C(=O)CCl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC1CN(C(=O)CN2CCN(c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)CC2)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine and MeCN was added to 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130 mg) and potassium carbonate (219 mg), followed by stirring at 80° C. for 3 hours. CHCl3 was added to the reaction mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 2-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}-1-(3-met hoxyazetidin-1-yl)ethanone (354 mg).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[OH2:14]>>[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[NH2:2][C@@H:1]1[CH2:7][C@H:4]([C:3]([OH:8])=[O:14])[CH:5]=[CH:6]1
Reactant: O=C1NC2C=CC1C2
Reactant: O
Agent: CS(=O)(=O)O
Product: N[C@H]1C=C[C@@H](C(=O)O)C1
Temperature: 35 °C
Yield: 0.6 %

Procedure:
A solution of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (97.45 g, 0.8929 mol, Enzymatix Ltd.) in tetrahydr n (500 mL) was filtered and warmed to 35° C. A solution of methanesulfonic acid (63.7 mL. 0.9817 mol) in water (24.1 mL, 1.34 mol) was added over the course of 1.5 hours such that the ensuing exotherm did not exceed 45° C. The resulting slurry was heated at 60° C. for three hours, then allowed to cool to room temperature over the course of 15 hours. The slurry was filtered and the cake washed twice with anhydrous tetrahydrofuran (200 mL). An analytical sample of the wet cake was removed and dried to give the title compound as a white solid (1.264 g); m.p. 167°-169.2° C.; 1H-NMR (DMSO-d6) δ: 12.6 (br s, 1H, CO2H), 8.04 (br s, 3H, NH3+), 6.10(dt, J=5.6,2.0,2.0 Hz, 1H, vinyl), 5.85 (dt, J=5.3,2.3,2.3 Hz, 1H, vinyl), 4.19 (br s, w1/2=20 Hz, 1H, allylic H), 3.61 (m, w1/2=22 Hz, 1H, allylic H), 2.53 (quintet, J=5.3 Hz (overlapping with DMSO peak), 1/2CH2), 2.39(s, 3H, CH3SO3H), 1.93 (dt, J=6.7,6.7,13.7 Hz, 1H, 1/2CH2); [α]20589 -83.8°, [α]20578 -87.4°, [α]20546 -101.2°, [α]20436 -186.7°, [α]20365 -316.2° (C=1.42, methanol); Cl-MS (CH4): 128(M+1); El-MS: 127(M).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][N:11]=1>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH3:7])=[CH:12][N:11]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccsc1Br
Product: COc1ccc(-c2sccc2C)cn1

Procedure:
The title intermediate, MS: m/e 206.1 (MH+), was prepared analogously to Example 52 from 2-bromo-3-methyl-thiophene and 2-methoxy-5-pyridineboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]([C:17]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=[O:27])[C:4]=2[CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1O2
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 70.3 %

Procedure:
A stirred mixture of 8-chloro-dibenz[b,f]-[1,4]oxazepine (3.35 g) and phthalic anhydride (2.13 g) in THF (40 mL) was heated to reflux for 4 days. The mixture was concentrated and the residue was triturated with ether. The precipitated solid was filtered to give the title compound as a white solid (3.84 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2SC)=[C:4]([F:21])[CH:3]=1.[CH2:22]([O:24][CH:25]([O:28][CH2:29]C)[CH2:26][NH2:27])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2[NH:27][CH2:26][CH:25]([O:28][CH3:29])[O:24][CH3:22])=[C:4]([F:21])[CH:3]=1
Reactant: CSc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Br)cc1F
Reactant: CCOC(CN)OCC
Product: COC(CNc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Br)cc1F)OC

Procedure:
3-(4-Bromo-2-fluorophenyl)-3,4-dihydro-2-methylthio-6-trifluoromethylpyrimidin-4-one (21.5 g) and aminoacetaldehyde diethyl acetal (15 g) were stirred for 3 hours at 130° C. The excess aminoacetaldehyde diethyl acetal was distilled off under reduced pressure and the residue was used in the next reaction as it was.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([F:12])=[CH:5][C:6]([CH3:11])=[C:7]([NH:9]N)[CH:8]=1.[O:13]1[CH:17]=[CH:16][CH2:15][CH2:14]1.Cl>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH3:11][C:6]12[C:16]([CH2:15][CH2:14][OH:13])=[CH:17][N:9]=[C:7]1[CH:8]=[C:3]([Br:2])[C:4]([F:12])=[CH:5]2
Reactant: C1=COCC1
Reactant: Cc1cc(F)c(Br)cc1NN
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC12C=C(F)C(Br)=CC1=NC=C2CCO
Temperature: 0 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To a solution of 5-bromo-4-fluoro-2-methylphenylhydrazine hydrochloride (4.75 g, 18.6 mmol) in 20% aqueous THF (100 mL) at 0° C. was added dropwise a solution of 2,3-dihydrofuran (1.55 mL, 20.4 mmol) in THF (10 mL). After stirring for 2 hours at 0° C. and 12 hours at room temperature, the reaction mixture was diluted with ether (100 mL). The organic solution was washed with saturated NaHCO3 (2×100 mL) and brine (100 mL), dried (Na2SO4) and concentrated. The residue was dissolved in ethylene glycol (50 mL), treated with ZnCl2 (5.58 g, 40.9 mmol), and heated at 170° C. for 4 hours. The reaction mixture was cooled down to room temperature and 6 N HCl (100 mL) was added. The mixture was extracted with ether (3×100 mL) and washed with water (200 mL) and brine (200 mL). The organic solution was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 1.52 g (30%) of title compound containing inseparable impurities (<20%) as a light brown oil. 1H NMR (CDCl3): 300 MHz δ 8.68 (bs, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.76 (d, J=9.63 Hz, 1H), 3.92 (t, J=6.48 Hz, 2H), 3.21 (t, J=6.48 Hz, 2H), 2.35 (s, 3H), 2.27 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C)C=O.[Cl:19]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[Cl:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1cc(Br)cc2cc[nH]c12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)cc2c(Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
To a solution of 12.00 g (49.8 mmol) of 5-bromo-7-nitro-1H-indole in 140 ml of tetrahydrofuran were added 1.4 ml of dimethylformamide and 6.98 g (52.3 mmol) of N-chlorosuccinimide followed by stirring at room temperature overnight. A 10% aqueous solution of sodium thiosulfate was added thereto followed by extracting with ethyl acetate. The organic layer was washed with water and brine successively, dr dried over magnesium sulfate and concentrated to dryness to give 14.84 g of the title compound.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[CH:20][C:19]=1[F:40]>>[CH3:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[C:19]([F:40])[CH:20]=2)=[O:25])[CH2:31][CH2:30]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)c(F)c3)CC2)c(C)c1
Yield: 13.4 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (1.07 g) described in Preparation Example 1 and (4-bromo-3-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.74 g) described in Preparation Example 132 and by the reaction and treatment in the same manner as in Example 32, the title compound (274 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11](OCC)=[O:12])=[CH:5][CH:4]=1)#[N:2].CC(C[AlH]CC(C)C)C>ClCCl.C1(C)C=CC=CC=1>[O:12]=[CH:11][C:10]#[C:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C#Cc1ccc(C#N)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C#CC=O)cc1
Yield: 36.6 %

Procedure:
To a solution of ethyl 3-(4-cyanophenyl)propiolate (2.2 g, 11.04 mmol, 1.00 equiv) in dichloromethane (10 mL) maintained under nitrogen at −65° C. was added a 25% DIBAL (22 mL, 2.00 equiv) solution in toluene dropwise with stirring. The resulting solution was stirred at −65° C. for 2 h and then quenched by the addition of 5 mL of saturated sodium potassium tartrate solution. The solid material was removed by filtration. The filtrate was extracted with 3×30 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of methanol in dichloromethane to give 627 mg (37%) of 4-(3-oxoprop-1-ynyl)benzonitrile as a white solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]2)=[C:32]([CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37])[CH:33]=1>C1(C)C=CC=CC=1>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]2)=[C:32]([CH:34]2[C:10]3([C:11]4[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:26])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:37][C:36](=[O:38])[NH:35]2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(Br)ccc1OC1CCN(C(=O)OC(C)(C)C)C1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)C1

Procedure:
In a manner similar to the method described in example 1e, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 5b (0.6 g, 1.5 mmol) was reacted with (R/S)-1-[5-bromo-2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (7.4 mmol) in toluene (30 mL) at 140° C. for 6 h to give racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.5 g, 48%)