Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[C:28]1([N:34]2[C:46]3[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=3[C:40]3[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.COCCOC>[C:28]1([N:34]2[C:46]3[CH:45]=[CH:44][C:43]([C:2]4[CH:3]=[CH:4][C:5]([C:8]5[C:21]6[C:16]([C:15]([C:22]7[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=7)=[C:14]7[C:9]=5[CH:10]=[CH:11][CH:12]=[CH:13]7)=[CH:17][CH:18]=[CH:19][CH:20]=6)=[CH:6][CH:7]=4)=[CH:42][C:41]=3[C:40]3[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)c3ccccc23)cc1
Temperature: 90 °C
Yield: 75 %

Procedure:
In a 200 mL three-neck flask were stirred 1.9 g (4.7 mmol) of 9-(4-Bromophenyl)-10-phenylanthracene (abbreviation: PA) obtained by the above Steps 1(1) to 1(4) described in Synthesis Example 1, 1.4 g (4.7 mmol) of 9-phenyl-9H-carbazol-3-boronic acid obtained by the above Step 1 described in Synthesis Example 2, 5.6 mg (25 μmol) of Palladium(II) acetate (abbreviation: Pd(OAc)2), 52 mg (170 μmol) of tris(o-tolyl)phosphine (abbreviation: P(o-tolyl)3), 7 mL (15 mmol) of potassium carbonate aqueous solution (2.0 mol/L), and 40 mL of 1,2-dimethoxyethane (abbreviation: DME) in a nitrogen atmosphere for 7 hours while being heated at 90° C. After that, the temperature of this suspending solution was cooled to room temperature, and the mixture was filtered to provide a residue. The obtained residue was dissolved into 50 mL of hot toluene, and the mixture was filtered through Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), alumina, and celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855) while 400 mL of toluene was added. The obtained filtrate was condensed, hexane was added therein, ultrasonic waves were applied thereto, and then recrystallization thereof was performed. Accordingly, 2.0 g of a powdery light-yellow solid of 9-phenyl-3-[4-(10-phenyl-9-anthryl)phenyl]-9H-carbazol (abbreviation: PCzPA), which was the object of the synthesis, was obtained in a yield of 75% (synthesis scheme (b-2)).
Reaction SMILES: N1C=C([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:8][CH:7]=2)C=N1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:49])[NH:44][CH2:43]3)O1>>[O:49]=[C:45]1[C:46]2[C:42](=[CH:41][C:40]([C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[C:9]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:24][CH2:23]5)=[CH:20][CH:21]=4)=[N:8][CH:7]=3)=[CH:48][CH:47]=2)[CH2:43][NH:44]1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: NC(=O)CN1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)CC1
Product: NC(=O)CN1CCC(c2ccc(Nc3ncc(-c4ccc5c(c4)CNC5=O)n4ccnc34)cc2)CC1

Procedure:
This compound may be prepared using the methods as described for Compound 224, using 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydroisoindol-1-one in Step 4. LCMS: Rt=0.79 min (100%), m/z (ESI) 483 (M+H)+.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH3:9][C:10]([C:19]1[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=1)([CH3:18])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].O>C(COC)OC>[CH3:18][C:10]([C:19]1[S:20][C:21]([N+:7]([O-:8])=[O:6])=[C:22]([CH3:24])[CH:23]=1)([CH3:9])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: O=[N+]=O
Reactant: Cc1csc(C(C)(C)C(=O)N2CCCC2)c1
Agent: F[B-](F)(F)F
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C(C)(C)C(=O)N2CCCC2)sc1[N+](=O)[O-]

Procedure:
Nitronium tetrafluoroborate (0.168 g, 1.26 mmol) was added to a solution of 1-[2-methyl-2-(4-methyl-2-thienyl)propanoyl]pyrrolidine (0.145 g, 0.61 mmol) in dimethoxy ethane (5 ml) cooled to −50 C. The mixture was allowed to warm to −30 C over 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and washed sequentially with a saturated solution of sodium bicarbonate and then with a saturated brine solution. The ethyl acetate solution was dried over magnesium sulfate and then evaporated to afford 1-[2-methyl-2-(4-methyl-5-nitro-2-thienyl)propanoyl]pyrrolidine as a yellow solid which was used in the next step without purification.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[C:26]3[C:22](C=[CH:24][NH:25]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:27]=[C:26]3[C:22]([C:7]([CH:6]=[O:10])=[CH:24][NH:25]3)=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
To a solution of DMF (5.0 mL, 64 mmol) and CH2Cl2 (120 mL) was added oxalyl chloride (2.1 mL, 24 mmol). The mixture was stirred for 45 minutes at ambient temperature and then was decanted into a solution of 6-(4-fluorophenyl)indole (5.1 g, 24 mmol), which was prepared as described in International Application Number PCT/US92/05890 (4 Feb. 1993). The reaction mixture was stirred for 90 minutes at ambient temperature and the imminium salt was isolated by filtration. The solids were dissolved in methanol (150 mL) and saturated aqueous NaHCO3 (200 mL) was added. The resulting precipitate was filtered and dried in a vacuum oven to give 6-(4-fluorophenyl)indole-3-carboxaldehyde (4.14 g, 72%) as a tan powder.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=C>>[CH2:14]([O:13]/[CH:3]=[CH:2]\[CH2:1][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:15][CH2:16][CH3:17]
Reactant: C=COCCCC
Reactant: C=CCNc1ccccc1
Product: CCCCO/C=C\CNc1ccccc1
Reaction time: 4 h
Yield: 52.3 %

Procedure:
Following the general procedure, N-allylaniline (50.0 mg, 0.375 mmol) was treated with butyl vinyl ether (376 mg, 3.75 mmol) and 5 mol % of in situ-generated complex 1a (188 μL, 0.10 M, 18.7 μmol; final substrate concentration=2.0 M) and allowed to stir for 4 h. The unpurified product is 96% Z (as determined by 400 MHz 1H NMR analysis). The resulting oil was purified by silica gel chromatography (50:1 hexanes:Et2O) to afford 8e (40.2 mg, 0.196 mmol , 52.0% yield, 96% Z isomer) as a light yellow oil. IR (neat): 3410 (br), 3048 (w), 2958 (m), 2932 (m), 2871 (m), 1660 (m), 1601 (s), 1503 (s), 1467 (m), 1431(w), 1375 (m), 1314 (m), 1250 (m), 1108 (s), 1094 (s), 1040 (m), 745 (s), 691 (s); 1H NMR (400 MHz, CDCl3): ™ δ 7.19-7.14 (2H, m), 6.72-6.67 (1H, m), 6.66-6.62 (2H, m), [diagnostic E isomer signal: 6.51 (1H, d, J=12.8 Hz)], 6.08 (1H, dt, J=6.4, 1.4 Hz), 4.51 (1H, td, J=6.6, 6.4 Hz), 3.82-3.74 (1H, m), 3.81 (2H, dd, J=6.8, 1.2 Hz), 3.79 (2H, t, J=6.4 Hz), 1.67-1.59 (2H, m), 1.47-1.37 (2H, m), 0.95 (3H, t, J=7.4 Hz); 13C NMR (100 MHz, CDCl3): ™ δ 148.5, 147.4, 129.3, 117.4, 113.2, 103.5, 72.6, 38.6, 32.0, 19.2, 14.0; HRMS (ESI+) [M+H]+ calcd for C13H20NO: 206.1545, found: 206.1541.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[NH:9][N:8]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:7]([NH2:6])[N:8]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[CH:18]=[CH:19]3)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1ccc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a mixed solvent of dimethylformamide (8 mL) and pyridine (0.47 mL) were added 3-amino-5-tert-butylpyrazole (810 mg), N-methylindol-5-boronic acid (780 mg), copper (II) acetate (790 mg) and molecular sieves (400 mg). The reaction mixture was stirred overnight at room temperature. The reaction mixture was added with 10% aqueous ammonia and filtered through Celite®. The filtrate was added with ethyl acetate and separated. The obtained organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=7:3→1:1→1:4) to give the titled compound (577 mg) having the following physical data.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6]C(=O)OC(C)(C)C)[CH2:2]1.[F:14][CH2:15][C:16](=O)[CH2:17][F:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:14][CH2:15][CH:16]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH2:6])[CH2:2]1)[CH2:17][F:18]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(CF)CF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N[C@@H]1CCN(C(CF)CF)C1
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.853 g). After stirring for one hour, the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL). The mixture was extracted with dichloromethane (25 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) and stirred for one hour. The mixture was concentrated to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13](O)[CH2:14][CH2:15]CCCCCCCCC>S(=O)(=O)(O)O.O.C1(C)C=CC=CC=1>[C:10]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:13][CH2:14][CH3:15].[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCO
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCC(=O)O
Temperature: 25 °C

Procedure:
16.52 g of phenylalanine was dissolved in a solution of 10 g of concentrated sulfuric acid, 20 mL water, 20 mL of dodecanol, and 120 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was then cooled to room temperature and washed with saturated aqueous sodium bicarbonate to neutralize acidic impurities, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to provide phenylalanine dodecanoate as a solid that was purified using a silica gel column eluted with a 1:9 methanol:dichloromethane mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[N:6]2[N:22]=[CH:23][CH:24]=[C:5]2[N:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[N:6]2[N:22]=[CH:23][CH:24]=[C:5]2[N:4]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)n2nccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCNCC2)n2nccc2n1
Yield: 75.3 %

Procedure:
tert-Butyl 4-(5-methoxy-pyrazolo[1,5-a]pyrimidin-7-yl)piperazine-1-carboxylate (1.186 g, 3.56 mmol) was stirred for 10 minutes at room temperature in a 1:1 mixture of dichloromethane and trifluoroacetic acid. The mixture was evaporated to dryness under reduced pressure, the residue was dissolved in water, the resulting solution was washed with dichloromethane, basified with 4M NaOH and extracted with dichloromethane (3×). The combined organic phases were washed with water, dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 624 mg of a solid (2.68 mmol, 75%). MS (APCI): m/z=234.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21][C:22]4[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=4[F:32])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1.[Cl:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([F:43])[CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[Cl:36][C:37]1[CH:38]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]3[C:17]4[C:12](=[CH:13][C:14]([S:18]([O:21][C:22]5[C:23]([F:32])=[C:24]([F:31])[C:25]([F:30])=[C:26]([F:29])[C:27]=5[F:28])(=[O:19])=[O:20])=[CH:15][CH:16]=4)[CH:11]=[CH:10][C:9]3=[O:33])[CH:7]=2)[CH:40]=[C:41]([F:43])[CH:42]=1
Reactant: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: OB(O)c1cc(F)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2cc(F)cc(Cl)c2)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 90 °C
Yield: 38.1 %

Procedure:
Perfluorophenyl 1-(5-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (15.00 g, 26.0 mmol), (3-chloro-5-fluorophenyl)boronic acid (4.99 g, 28.6 mmol), potassium carbonate (10.79 g, 78 mmol), and Pd(PPh3)4 (3.01 g, 2.60 mmol) were combined in 1,4-dioxane (98 ml) and water (32.5 ml). The reaction was heated to 90° C. for 2.5 h. After cooling to room temperature, the reaction was diluted with DCM and washed with water. The organics were dried via phase separator and concentrated in vacuo. The crude oil was dry loaded onto silica gel and purified via MPLC, eluting with 0-100% ethyl acetate (with a 10% DCM additive) to yield perfluorophenyl 1-(3′-chloro-5′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (6.20 g, 9.91 mmol, 38.1% yield) as a beige solid. m/z (ESI) 626.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH:25]=[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]=2[CH2:30][O:29][C:28]2[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][CH:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[N:36][C:31]=4[CH2:30][O:29][C:28]4[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(C#N)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4-(4-chloro-phenyl)-piperidine-4-carbonitrile (180 mg, 0.8 mmol) in acetonitrile/water (4/1) was added potassium carbonate (221 mg, 1.6 mmol), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporated from the combined dried (MgSO4) organic extracts, and the residue was purified by column chromatography on silica gel using hexane-ethyl acetate (6:4) to afford the title compound.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH:8]=[C:7]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N+:20]([O-])=O)[CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]([CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=3)[NH2:20])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cc(C2=CCN(C3CC3)CC2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C2CCN(C3CC3)CC2)cc(C(F)(F)F)c1
Yield: 93.4 %

Procedure:
Stir the mixture of Pd/C (10%, 30 mg), 1-cyclopropyl-4-(3-nitro-5-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine (120 mg 0.32 mmol) in methanol (10 mL) under hydrogen atmosphere at room temperature for 18 hrs. Remove hydrogen atmosphere, filter off the solid, concentrate the filtrate to yield the product as a white solid (85 mg, 94%). MS: (M+1): 285.1.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([OH:4])=[O:3].[Cl:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CC[O-].[Na+]>>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([Cl:7])[C:1](=[O:6])[C:2]([OH:4])=[O:3])[CH3:13]
Reactant: O=C(O)C(=O)O
Reactant: CCOC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(Cl)C(=O)C(=O)O

Procedure:
by ester condensation, e.g. by the reaction of oxalic acid or its diethylester with ethyl chloroacetate in the presence of sodium ethylate, α-chloro-β-keto-succinic acid ethyl ester is obtained in accordance with the following reaction scheme:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][CH3:20])[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][CH3:20])[S:15]1)=[O:11]
Reactant: CN=C=O
Reactant: CCSc1nc(O)ns1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
10.4 ml of triethylamine and 10 ml of methyl isocyanate were added to a solution of 20.3 g of 3-hydroxy-5-ethylthio-1,2,4-thiadiazole in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C for 1 hour, cooled to -10° C and filtered. The product was crystallized from ethyl acetate to obtain 18 g of 2-(N-methylcarbamoyl)-5-ethylthio-1,2,4-thiadiazole-3-one melting at 131° C.
Reaction SMILES: [CH:1]1([CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.CO>[Pd].C(OCC)(=O)C>[CH:1]1([CH2:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: CN(c1cc(C=CC2CC2)cc(C(=O)O)c1)S(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1cc(CCC2CC2)cc(C(=O)O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A mixture of 3-(2-cyclopropylvinyl)-5-[methyl(methylsulfonyl)amino]benzoic acid obtained in Reference Example 23 89 mg (0.30 mmol), 10% Pd/C (50% wet) 30 mg, methanol (1 mL) and ethyl acetate (1 mL) was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The reaction solution was filtered on Celite and the solvent was evaporated to give 89 mg (0.30 mmol, 100%) of the title compound (yield: 100%).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=O)=[CH:8][C:7]([Cl:21])=[C:6]([O:22][CH3:23])[CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:21][C:7]1[CH:8]=[C:9]2[C:4]([C:1]([OH:3])=[CH:2][C:11]([C:13]3[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=3)=[N:10]2)=[CH:5][C:6]=1[O:22][CH3:23]
Reactant: COc1cc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)cc1Cl
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1cc2c(O)cc(-c3nc(C(C)C)cs3)nc2cc1Cl
Yield: 70 %

Procedure:
Compound 218g was synthesized from compound 217g as a yellow solid in 70% yield, according to the procedures as described for compound 218a. MS (ESI, EI+): m/z=335 (MH+).
Reaction SMILES: [BH4-].[Na+].[Cl-].[Cl-].[Cl-].[Al+3].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OC)=[O:19]>COCCOCCOC>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]
Reactant: COC(=O)CCCCCCCCCCBr
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: COCCOCCOC
Product: OCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Sodium Borohydride (16.32 g, 0.43 mole) was dissolved in diglyme (350 ml). To this was added a solution of aluminium trichloride (19.2 g, 0.14 mole) in diglyme (250 ml) maintaining the temperature below 20°. After the addition was complete, the mixture was stirred for 0.5 hour at room temperature. The reducing agent was then added dropwise to a solution of methyl 11-bromoundecanoate* (120 g, 0.43 mole) in diglyme (200 ml) maintaining the temperature at 10°. After the addition was complete the reaction was stirred at 20° for 3 hours and then quenched by pouring onto water (2 L) and concentrated HCl (100 ml). The quenched mixture was stirred for 1 hour then cooled to 15°. The product was filtered off, washed with water (2×500 ml) and dried under vacuum to give 11-bromoundecanol (106.8 g, 98.9%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16](B(O)O)[CH:17]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=1[C:21]([F:22])([F:23])[F:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(F)ccc1C(F)(F)F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1cc(F)ccc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 45.9 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 400 mg, 2.74 mmol), 5-fluoro-2-(trifluoromethyl)phenylboronic acid (Cuschem, Inc., Yonkers, N.Y.; 512 mg, 2.46 mmol), copper(II) acetate (497 mg, 2.74 mmol) and triethylamine (380 μL, 2.7 mmol) in 1,2-dichloroethane (18 mL) was heated in an oil bath at 50° C. for 2 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(5-fluoro-2-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (348 mg, 41%) as a colorless oil that solidified.
Reaction SMILES: [C:1]([N:9]1[CH2:27][CH2:26][C:12]2[N:13]([CH2:20][C:21]([O:23]CC)=[O:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.O>[C:2]1([C:1]([N:9]2[CH2:27][CH2:26][C:12]3[N:13]([CH2:20][C:21]([OH:23])=[O:22])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[O:8])[C:7]2[C:6](=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)c1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1c2c(c3ccccc31)CN(C(=O)c1cccc3ccccc13)CC2

Procedure:
Step b): A solution of crude ethyl (2-benzoyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate (0.085 mmol) in THF (0.5 ml) is treated with 0.2 N aqueous NaOH solution (0.64 ml) at rt for 15 min. Then, the yellow reaction mixture is diluted with water (2 ml), washed with diethyl ether (2 ml), acidified with conc. HCl to pH 1 and extracted with dichloromethane. The combined organic phases are washed with water, then dried over Na2SO4, filtered and the solvent evaporated. The crude product is recrystallized from diisopropyl ether to give pure title compound as yellow solid: tR (LC-1) 2.95 min; ESI-MS positive ion): m/z 335.17 [M+H]+ (calcd 334.37 for C20H18N2O3).