Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.O=S(Cl)[Cl:22]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:22])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C=CC(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
A first 3 L, 4 necked round bottomed flask (RBF) was equipped with a mechanical stirrer, thermowell, and a condenser with nitrogen adapter. The RBF was charged with 4-methoxycinnamic acid (175 g, 982 mmol) and 0.1 mL dry pyridine in 2 L dry toluene. The addition funnel was charged with 107.2 mL (1.473 mol) SOCl2 which was then added slowly to the reaction mixture at room temperature. The reaction mixture was heated to reflux and monitored by GC analysis (aliquots were withdrawn periodically, quenched with MeOH, and analyzed). After 5 hours, the GC analysis indicated that the reaction was complete and the reaction mixture was allowed to cool to room temperature. Excess SOCl2 and toluene were removed by rotary evaporation and the crude product was purified by distillation to give 182 g of 4-methoxycinnamoyl chloride (94% yield) with 98.9% purity by GC.
Reaction SMILES: [C:1]([C:3]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][CH:5]([N:7]([CH3:16])C(=O)OCC(Cl)(Cl)Cl)[CH3:6])#[N:2].C(O)=O>O1CCCC1.[Zn]>[CH3:30][O:29][C:25]1[CH:24]=[C:23]([C:3]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:4][CH:5]([CH3:6])[N:7]([CH3:16])[C:1]2=[NH:2])[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(C(C#N)(CC(C)N(C)C(=O)OCC(Cl)(Cl)Cl)c2ccccc2)c1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O=CO
Product: COc1cccc(C2(c3ccccc3)CC(C)N(C)C2=N)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product of Step 3 (40 g) was dissolved in tetrahydrofuran (500 mL). The solution was cooled to 0° C. using ice bath and stirred under Argon for 30 min. Then, 60 g zinc dust followed by 60 mL of formic acid (90%) was added to the reaction mixtures and stirring continued at 0° C. for 3 hr under argon purging. The stifling was continued at 25° C. for 16 hr under argon purging. Then, the reaction mixture was filtered and concentrated under vacuum. Crude Step 4 product was carried forward without purification.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][N:8]([CH3:10])[CH3:9])=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:4]1[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[S:1][C:5]=1[CH2:6][CH2:7][N:8]([CH3:10])[CH3:9]
Reactant: BrBr
Reactant: CN(C)CCc1cc2ccccc2s1
Solvent: ClC(Cl)Cl
Product: CN(C)CCc1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of Compound 1a (2-Benzo[b]thiophen-2-yl-ethyl) -dimethyl-amine (39 mmol) in chloroform (500 mL) was added Br2 (43 mmol) dropwise. The mixture was stirred overnight at RT and subsequently washed with sat. NaHCO3 (3×) and brine, dried (MgSO4) and concentrated in vacuo. The crude material was purified by silica gel column chromatography in EtOAc to afford [2-(3-Bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine, Compound 2a, as an oil (9.6 g, 86%); MS (MH+) 283.9.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:39])[C@@H:10]([NH:22][C:23]([N:25]1[CH2:34][CH2:33][C:32]2[CH:31]=[N:30][C:29]([NH:35][CH:36]([CH3:38])[CH3:37])=[N:28][C:27]=2[CH2:26]1)=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=1[F:21])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:21][C:12]1[C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=[CH:16][C:11]=1[C@H:10]([NH:22][C:23]([N:25]1[CH2:34][CH2:33][C:32]2[CH:31]=[N:30][C:29]([NH:35][CH:36]([CH3:38])[CH3:37])=[N:28][C:27]=2[CH2:26]1)=[O:24])[C@@H:9]([OH:8])[CH3:39]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1cccc(C(F)(F)F)c1F)[C@@H](C)O[Si](C)(C)C(C)(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1cccc(C(F)(F)F)c1F)[C@H](C)O)CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 116 (533 mg, 0.936 mmol) and THF (10 mL) cooled to 0° C. was added TBAF (1.310 mL, 1.31 mmol) and reaction was stirred at RT for 45 min. The reaction was poured onto water and extracted with DCM. The organic layer was concentrated and the crude product was purified by SiO2 chromatography eluting with 1% MeOH/DCM to afford 269 mg (63.1%) of I-18: LCMS (ACPI-pos) m/z 420.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3)cc2N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
A mixture of the product from Example 232b (56 mg, 0.17 mmol), benzyl bromide (21 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (62 mg, 100%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:41]1([CH2:46][CH2:47][CH2:48][S:49]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][N:60]=3)=[CH:54][CH:53]=2)(=[O:51])=[O:50])[CH2:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl.CN(C=O)C>[N:41]1([CH2:46][CH2:47][CH2:48][S:49]([C:52]2[CH:53]=[CH:54][C:55]([NH:58][C:59]3[N:60]=[CH:61][C:62]([NH:65][C:12](=[O:14])[C:11]4[CH:15]=[CH:16][CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:22])[F:21])[CH:4]=5)[CH:10]=4)=[CH:63][N:64]=3)=[CH:56][CH:57]=2)(=[O:50])=[O:51])[CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: O=C(O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Reactant: Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 51.1 %

Procedure:
To a solution of intermediate 5 (Example 9) (240 mg, 0.8 mmol) in anhydrous CH2Cl2 (15 mL), 2-chloro-4,6-dimethoxy-1,3,5-triazine (170 mg, 1 mmol) and 4-methylmorpholine (160 mg, 1.6 mmol) were added. After the reaction mixture was stirred at room temperature for 75 minutes, intermediate 2 (Example 3) (100 mg, 0.3 mmol) in anhydrous DMF (2.5 mL) was added into the solution. The solution was stirred under argon for overnight. The residue was dissolved in CH2Cl2 (20 mL) and washed with aqueous saturated NaHCO3 solution (20 mL). The aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic phase was dried (Na2SO4) and the solvent was removed. The crude product was purified by silica gel column with CHCl3 to 10% CH3OH/CHCl3 as eluents to give the final product as a pale yellow solid (100 mg, 19%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16](=[O:26])[N:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[N:13]=[C:12]1[C:27]1[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:28]=1[C:29](O)=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:40]([O:47][CH2:48][C@@H:49]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][NH:50]1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16](=[O:26])[N:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[N:13]=[C:12]1[C:27]1[CH:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][C:28]=1[C:29]([N:50]1[C@H:49]([CH2:48][O:47][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51]1)=[O:30])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCCCN(CCCC)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1Cc2ccccc2CN1
Product: CCCCN(CCCC)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Yield: 85.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271H, 2-(1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (105 mg, 0.19 mmol) and (S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline (62 mg, 0.22 mmol) were converted to the title compound (133 mg, 87%). MS(ESI+) m/z 820.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[C:13]([NH:18][NH:19][C:20](Cl)=[O:21])([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([NH:8][C:20](=[O:21])[NH:19][NH:18][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: CCOC(=O)NNC(=O)Cl
Reactant: Nc1c(F)c(F)c(F)c(F)c1F
Solvent: Cc1ccccc1
Product: CCOC(=O)NNC(=O)Nc1c(F)c(F)c(F)c(F)c1F

Procedure:
Pentafluoroaniline (17 g, 0.106 mol) is dissolved in 300 ml of toluene with heating. The 2-carbethoxyhydrazinecarbonyl chloride, 19.4 g (0.122M) is added to the hot solution. The mixture is refluxed until a white solid precipitates. The solid is filtered to give 24.8 g. The product is crystallized by dissolving in ethyl acetate/toluene (1/2 by vol) and evaporating until crystals appear, mp 180°-182°.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20](OCC)C.[Si](C=[N+]=[N-])(C)(C)C.CC(O)=O>ClCCl.CO>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:20])=[O:12])=[CH:9][C:8]=2[C:16]([F:17])([F:18])[F:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOCC
Reactant: O=C(O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Yield: 95 %

Procedure:
To a stirred solution of 4-cyclohexyl-3-(trifluoromethyl)benzoic acid (Preparation 118B, 0.5 g, 1.836 mmol) in dichloromethane (2 mL) and MeOH (2 mL) was added 2M diethyl ether solution of TMS-diazomethane (1.836 mL, 3.67 mmol) dropwise at 0° C. till no gas evolved. The mixture was stirred at room temperature for 1 hr before AcOH (0.210 mL, 3.67 mmol) was added at 0° C. to quench the reaction. The mixture was concentrated. To the residue was added saturated aqueous sodium bicarbonate solution (5 mL) and extracted with dichloromethane (3×3 mL). The combined dichloromethane extracts were dried (sodium sulfate) and concentrated under reduced pressure to give a liquid. Flash chromatography purification (silica gel column, 10→40% dichloromethane in n-heptane) afforded methyl 4-cyclohexyl-3-(trifluoromethyl)benzoate (0.5 g, 1.746 mmol, 95% yield) as a colorless liquid. The compound had an HPLC retention time=4.03 min. (condition C); LC/MS M+1=287.2.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19]3=[N:22][C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][N:18]3[C:17]2=[O:33])=[CH:12][CH:11]=1>C(#N)C.C(O)(=O)C.C(Cl)Cl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19]3=[N:22][C:23]([CH2:25][O:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:24]([I:1])[N:18]3[C:17]2=[O:33])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)cn21
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)c(I)n21
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.1 %

Procedure:
N-iodosuccinimide (73.4 mg, 0.33 mmol) was added to a stirred solution of 6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (0.1 g, 0.3 mmol) in a mixture of ACN (2 mL) and acetic acid (2 mL). The mixture was stirred at RT for 3 days. The mixture was diluted with DCM and washed with a saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was triturated with MeOH to yield 6-(4-fluoro-phenyl)-3-iodo-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (46 mg, 56% yield) as a brown solid, that was used in the next step without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.Br[C:26]1[CH:27]=[C:28]2[C:33]3=[C:34]([CH2:36][CH2:37][CH2:38][N:32]3[CH:31]=[C:30]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]2=[O:44])[CH:35]=1.[C:45]([O:49][C:50]([NH:52][CH2:53][C:54]#[CH:55])=[O:51])([CH3:48])([CH3:47])[CH3:46]>O1CCCC1.C(NCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu](I)I>[C:45]([O:49][C:50]([NH:52][CH2:53][C:54]#[C:55][C:26]1[CH:27]=[C:28]2[C:33]3=[C:34]([CH2:36][CH2:37][CH2:38][N:32]3[CH:31]=[C:30]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:29]2=[O:44])[CH:35]=1)=[O:51])([CH3:48])([CH3:47])[CH3:46]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cn2c3c(cc(Br)cc3c1=O)CCC2
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCOC(=O)c1cn2c3c(cc(C#CCNC(=O)OC(C)(C)C)cc3c1=O)CCC2
Temperature: 0 °C

Procedure:
A yellow suspension of palladium acetate (73 mg, 0.32 mmol) and triphenylphosphine (191 mg, 0.72 mmol) in dry tetrahydrofuran (6 mL) under argon was cooled to 0° C. A solution of n-butyllithium (2.5M in hexanes, 284 uL) was added dropwise and after 15 minutes the dark green suspension is warmed to room temperature for 15 minutes. This suspension is then cannulated under argon into a white suspension of ethyl 9-bromo-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate (337 mg, 1 mmol), copper iodide (84 mg, 0.44 mmol) and t-butoxycarbonylpropargylamine (198 mg, 1.28 mmol) in diethylamine (6 mL). The brown suspension is warmed to 45° C. for 2 hours then filtered off and preabsorbed on silica gel. Chromatography on silica gel eluting with 0-5% (9:1 MeOH/20 M NH3) in dichloromethane provided the title compound as a brown oil. ESMS m/z 411 (MH+). 1H NMR (CDCl3) δ 8.23(s, 1H), 8.12 (d, 1H), 7.29 (d, 1H), 5.1 (m, 1H), 4.35 (q, 2H), 4.15 (m, 2×2H), 2.97 (t, 2H), 2.19 (tt, 2H), 1.49 (s, 9H), 1.38 (t, 3H).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[NH:23]1[C:27](=[O:28])[CH2:26][CH2:25][CH:24]1[C:29]([OH:31])=[O:30].N12CCCN=C1CCCCC2>CN(C)C=O>[O:28]=[C:27]1[NH:23][CH:24]([C:29]([O:31][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:30])[CH2:25][CH2:26]1
Reactant: O=C1CCC(C(=O)O)N1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)N1
Yield: 69.4 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), DL-pyroglutamic acid (3.9 g) and 1,8-diazabicyclo[5.4.0]-undec-7ene (4.6 g). After recrystallization in dimethylformamide, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-oxo-2-pyrrolidinecarboxylate (8.8 g), m.p. 255° C. (decomposition), is obtained.
Reaction SMILES: I[CH2:2][CH:3]1[O:7][CH:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.CCOC(C)=O>[N:17]([CH2:2][CH:3]1[O:7][CH:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:5][CH2:4]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(CI)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 36 h
Yield: 100.2 %

Procedure:
To a solution of 5-(5-(iodomethyl)tetrahydrofuran-2-yl)-1-methyl-4-nitro-1H-pyrazole (640 mg, 1.90 mmol, intermediate 60) in dry DMF (10 mL) was added sodium azide (250 mg, 3.80 mmol) and the mixture stirred at room temperature for 36 hr. The mixture was diluted with EtOAc (25 mL) and washed with water (2×10 mL) and brine (20 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure to give 5-(5-(azidomethyl)tetrahydrofuran-2-yl)-1-methyl-4-nitro-1H-pyrazole as a yellow oil (480 mg, 100%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 5.84-5.70 (m, 1H), 4.49-4.45 (m, 1H), 4.03 (s, 3H), 3.56-3.39 (m, 2H), 2.66-2.65 (m, 1H), 2.29-2.22 (m, 1H), 2.02-1.92 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(CCO)=CC=CC=1.O.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>[CH2:29]([O:28][CH2:27][CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][CH2:9][CH2:8][C:7](=[O:15])[C:6]=3[CH:16]=2)=[CH:24][CH:23]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CCCN1CCCC(=O)c2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C(=O)CCCN3CCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 7-bromo-1-propyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-one (5.89 g), 4-(2-butoxyethoxy)phenyl borate (5.45 g) and potassium carbonate (5.74 g) in toluene-ethanol-water (200-20-20 ml) was stirred at room temperature for 1 hour under argon atmosphere. To the reaction system was added tetrakistriphenylphosphinepalladium (0.72 g), and the mixture was heated to reflux for 3 hours. After cooled to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:9→1:4) to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-one (7.15 g) as yellow oil.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:4]=2[CH:3]=1.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[Sn](CCCC)(CCCC)CCCC>>[Br:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:2]([C:22]4[N:21]([CH3:20])[CH:25]=[CH:24][CH:23]=4)=[CH:3][C:4]=3[C:5]2([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(-c3cccn3C)cc21

Procedure:
As shown in scheme 2, 2,7-dibromo-9,9-diethyl-9H-fluorene (21) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain 2-(7-bromo-9,9-diethyl-9H-fluoren-2-yl)-1-methyl-1H-pyrrole (22). Then, in the presence of sodium tert-butoxide, Pd(dba)2, and tri-tert-butyl phosphine, 2-(7-bromo-9,9-diethyl-9H-fluoren-2-yl)-1-methyl-1H-pyrrole (22) is reacted with diphenylamine to obtain 9,9-diethyl-7-(1-methyl-1H-pyrrol-2-yl)-N,N-diphenyl-9H-fluoren-2-amine (23a). n-butyl lithium is reacted with 9,9-diethyl-7-(1-methyl-1H-pyrrol-2-yl)-N,N-diphenyl-9H-fluoren-2-amine (23a), and then tributylstannylchloride is added thereto to obtain N-methyl-2-(7-diphenyl-amino-9,9-diethyl-9H-fluoren-2-yl)-5-tributylstannylpyrrole (24a). N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)-5-tributyl-stannylpyrrole (24a) is reacted with 5-bromo-2-thiophene carboxaldehyde by Stille coupling reaction to obtain 5-[N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (25a). Finally, 5-[N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (25a) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[5-(N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)pyrrol-5-yl)thiophen-2-yl]acrylic acid (26a) is obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cc(F)ccc4F)c3O2)cc1
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.045 g, 58%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.12 g, 3.9 mmol). mp 138-140° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1F
Temperature: 25 °C

Procedure:
15.4 g of 2-fluoro-4-methylbenzoic acid was dissolved in 200 mL of methanol, and 10.0 mL of concentrated sulfuric acid was added thereto, followed by heating with reflux overnight. The reaction liquid was cooled to room temperature and then concentrated to about 50 mL, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 90:10) to obtain 15.2 g of methyl 2-fluoro-4-methylbenzoate.