Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCCO)C.C(OCC)C>[ClH:20].[F:1][C:2]1[CH:18]=[CH:17][C:16]2[NH+:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[CH:3]=1
Reactant: Cn1c2c3ccccc3nc-2c(Cl)c2cc(F)ccc21
Reactant: Nc1ccccc1
Solvent: CCOCC
Solvent: CCOCCO
Product: C[NH+]1C2=c3ccccc3=NC2=C(Nc2ccccc2)c2cc(F)ccc21
Product: Cl
Yield: 81.8 %

Procedure:
A solution of 2-fluoro-5-methyl-11-chloroquindoline from Example 24 (530 mg, 1.79 mmol) and aniline (0.75 g, 8.06 mmol) in EtOCH2CH2OH (50 mL) was heated at 120° C. for 10 min. During this time the color of the reaction mixture changed from purple to yellow, and a yellow precipitate formed. After cooling, the reaction mixture was diluted with diethyl ether (100 mL) and the precipitate was collected, washed thoroughly with diethyl ether and dried, providing 555 mg (79.4%) of the title compound, mp 280° C. (sublimed); 1H NMR (DMSO-d6) δ 11.26 (s, NH), 10.62 (s, NH), 8.64 (d, J=8.0, 2H), 8.46 (d, J=9.2, 1H), 8.04 (t, J=8.0, 1H), 7.77-7.68 (m, 2H), 7.47-7.39 (m, 3H), 7.29-7.22 (m, 3H), 4.81 (s, 3H); 13C NMR (acetone-d6) δ 152.50 (d, J=259.5), 136.01, 132.03 (d, J=2.96), 130.95, 130.52, 127.76, 125.68, 123.12, 119.52, 117.72, 115.57, 115.32, 115.08, 113.86 (d, J=9.6), 113.37, 112.07 (d, J=9.7), 107.81, 106.57, 101.60 (d, J=26.2), 32.13; MS (EI, m/z) 340 (M+).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][N:10]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:29]>O>[C:1]1([S:7]([CH2:8][CH2:9][N:10]([CH2:23][C:24]([F:27])([F:25])[F:26])[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:20])([F:21])[F:22])[CH:12]=2)=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: N#Cc1ccc(N(CCSc2ccccc2)CC(F)(F)F)cc1C(F)(F)F
Solvent: O
Product: N#Cc1ccc(N(CCS(=O)c2ccccc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 4-[[2-(phenylthio)ethyl](2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.039 g, 0.096 mmol) in MeOH (3 mL) was added a solution of NaIO4 (0.041 g, 0.193 mmol) in water (1 mL) and stirred at rt. After 1 h, additional NaIO4 (0.041 g, 0.19 mmol) dissolved in water (1 mL) was added and the reaction mixture diluted with MeOH (1 mL). After stirring at rt for 12 h, the mixture was partitioned between EtOAc and brine. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (1-10% MeOH/CH2Cl2 gradient) to give the title compound (0.037 g, 88% yield): MS (ES) m/z 421 (M+1).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][C@H:10]2[CH2:15][O:14][CH2:13][CH2:12][N:11]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.Cl[C:33](=[O:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C1COCC1>[O:39]=[C:33]([N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:9][C@H:10]1[CH2:15][O:14][CH2:13][CH2:12][N:11]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C(=O)Cl
Reactant: c1ccc(CNC[C@H]2COCCN2Cc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)N(Cc1ccccc1)C[C@H]1COCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 1-phenyl-N-{[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}methanamine (assumed 87.79 g, 296.2 mmol) and N,N-diisopropylethylamine (67.1 mL, 385.2 mmol) in THF (1000 mL) was cooled to 0° C. To the solution was added ethyl chloro(oxo)acetate (36.3 mL, 326.2 mmol) dropwise via addition funnel. The resulting mixture was allowed to stir and warm to room temperature for 1 h. The solvent was then removed in vacuo to approximately 20% volume, and the residue was partitioned between EtOAc (600 mL), water (100 mL) and sat. aqueous NaHCO3 (500 mL). The aqueous phase was extracted with a fresh portion of EtOAc (200 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was then azeotroped with EtOH (100 mL) to provide ethyl oxo((phenylmethyl){[(3S)-4-(phenylmethyl)-3-morpholinyl]methyl}amino)acetate as a yellow oil that was used without further purification. LCMS: (M+H)+: 397.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:12]([O:14][C:15](=[O:21])[CH2:16][N:17]([C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[CH:18]([CH3:20])[CH3:19])[CH3:13]
Reactant: CCOC(=O)CNC(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Yield: 72 %

Procedure:
2,4-Dichloro-5-nitro-pyrimidine (40 g; 0.207 mol) was added to a cooled (0-10° C.) solution of isopropylamino-acetic acid ethyl ester (30 g; 0.207 mol) in 300 ml of acetone. A solution of potassium carbonate (28.5 g; 0.207 mol) in water was then added to the cooled reaction mixture. The reaction mixture was allowed to reach room temperature and was maintained at that temperature until complete conversion of the starting material into the desired product.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([Cl:21])[Cl:20])=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:20][C:19]([Cl:21])=[CH:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: O=C(Oc1ccc(OCC=C(Cl)Cl)cc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCC=C(Cl)Cl)cc1
Reaction time: 1 h
Yield: 87 %

Procedure:
A reaction vessel was charged with 44.1 g of 4-(3,3-dichloro-2-propenyl-oxy)phenyl benzoate and 400 ml of methanol, to which 33 g of 30% potassium hydroxide solution was slowly added dropwise under ice cooling. After stirring for 1 hour, the reaction mixture was made weakly acidic by the addition of 10% hydrochloric acid, and extracted twice with 150 ml of diethyl ether under salting out. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 26.0 g of 4-(3,3-dichloro-2-propenyloxy)phenol (87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=2)[N:7]([CH:20]([CH3:22])[CH3:21])[CH:6]=1)=[O:4].[F:23][C:24]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].COC(C1C=C(Br)N(C(C)C)C=1)=O.ClC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=2)[N:7]([CH:20]([CH3:22])[CH3:21])[C:6]=1[CH:32]([C:30]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([F:23])[CH:31]=1)[OH:33])=[O:4]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: COC(=O)c1cc(-c2cnc(OC)nc2OC)n(C(C)C)c1
Agent: COC(=O)c1cc(Br)n(C(C)C)c1
Agent: O=Cc1ccc(Cl)cc1
Product: COC(=O)c1cc(-c2cnc(OC)nc2OC)n(C(C)C)c1C(O)c1ccc(C#N)c(F)c1

Procedure:
The title compound was prepared in analogy to the procedure described for Step D3 but 5-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step 195.3) and 2-fluoro-4-formyl-benzonitrile [101048-76-4] were used instead of 5-bromo-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 4-chlorobenzaldehyde respectively. The title compound was obtained as a yellow solid. tR: 1.12 min (HPLC 3); ESI-MS: tR=1.11 min, [M+H]+ 455 (LC-MS 1); TLC: Rf=0.30 (1:1 EtOAc/heptanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3=[N:13][N:14]=[N:15][N:11]3[CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1.[CH3:17][O:18]C1C=C2C(=CC=1C=O)N1N=NN=C1CC2>>[CH3:1][O:2][C:3]1[C:4]([CH:17]=[O:18])=[CH:5][C:6]2[C:12]3=[N:13][N:14]=[N:15][N:11]3[CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1C=O)-n1nnnc1CC2
Reactant: COc1ccc2c(c1)CCCn1nnnc1-2
Product: COc1cc2c(cc1C=O)-c1nnnn1CCC2

Procedure:
This compound was prepared from Compound 9 in the same manner of Compound 2.
Reaction SMILES: O/[CH:2]=[CH:3]/[C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[CH3:14][NH:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:14][N:15]([CH3:16])/[CH:2]=[CH:3]/[C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(/C=C/O)Cc1ccccc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A solution of (3E)-4-hydroxy-1-phenylbut-3-en-2-one (1.2 g, 7.4 mmol) in THF (20 mL) was added dimethylamine hydrochloride (1.8 g, 22.2 mmol), K2CO3 (6.1 g, 44.4 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated and purified by flash column chromatography (PE/EtOAc=10:1) to give the title compound (0.6 g, 43%) as a yellow oil. [M+H] Calc'd for C12H15NO, 190. Found, 190.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)[CH:11]=1.CCN=C=NCCCN(C)C.Cl.[NH2:44][CH2:45][C@H:46]([OH:49])[CH2:47][OH:48]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[OH:49][C@H:46]([CH2:47][OH:48])[CH2:45][NH:44][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][N:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: NC[C@H](O)CO
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Reaction time: 25 h
Yield: 53.5 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.07 g, 2.39 mmol) synthesized in Example (97e) was dissolved in methylene chloride (20 mL), and WSCI•HCl (732 mg, 3.82 mmol), (S)-(−)-3-amino-1,2-propanediol (500 mg, 5.49 mmol) and 4-dimethylaminopyridine (146 mg, 1.19 mmol) were added at room temperature, followed by stirring for 25 hours under nitrogen atmosphere. The reaction solution was diluted with ethyl acetate (50 mL), washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired product (666 mg, 54%) as a white solid.
Reaction SMILES: Cl.O=[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:4]1[CH2:5][C@H:6]1[CH2:10][O:9][CH2:8][N:7]1[C:11](=[O:22])[CH2:12][N:13](C)[C:14](OC(C)(C)C)=O.C(O)(C(F)(F)F)=[O:28]>CCOCC>[CH3:14][NH:13][CH2:12][C:11]([N:7]1[C@@H:6]([CH2:5][C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:3]=2)[CH2:10][O:9][C:8]1=[O:28])=[O:22]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(CC(=O)N1COC[C@@H]1CC1C=CC=CC1=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CNCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
HCl gas was bubbled into a solution of N-{2-[(4S)-2-oxo4-benzyl(1,3-oxazolidin-3-yl)]-2-oxoethyl}(tert-butoxy)-N-methylcarboxamide (7.2 g, 21 mmol) in Et2O (150 mL) over 30 min. The resulting white slurry was stirred for 2 h, allowed to warm to room temperature, and stirred for 2 h. A solution of HCl (1M in Et2O, 20 mL, 20 mmol, 3.6 equiv) was added and the reaction mixture was stirred overnight, then treated with TFA (10 mL), and stirred for 2 h. HCl gas was again bubbled into the mixture over 15 min, and the reaction was stirred for 3 h. The resulting mixture was concentrated under reduced pressure and the residue was triturated (100 mL of 50% EtOAc/hexanes). The resulting precipitate was filtered and washed with hexanes to give (4S)-3-[2-(methylamino)acetyl]-4-benzyl-1,3-oxazolidin-2-one (5.69 g, 96%) as a white solid: 1H NMR (CDCl3) δ 2.62 (br s, 3H), 2.91-3.04 (m, 2H), 4.22-4.44 (m, 4H), 4.65-4.73 (m, 1H), 7.22-7.34 (m, 5H), 9.26 (br s, 2H); HPLC ES-MS m/z (rel abundance) 249 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16](Br)[CH:15]=2)[C:7]=1[F:23])[CH3:2].[C:25]1(C)C=CC=C[CH:26]=1.C(C([Sn])=C(CCCC)CCCC)CCC>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.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:15]=[C:16]([CH:25]=[CH2:26])[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=2)[C:7]=1[F:23])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: CCOC(C)=O
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CC(=O)OCC)c2F)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
A 2-necked flask was equipped with a reflux condenser and charged with 117c (1.14 g, 2.78 mmol) and tetrakis(triphenylphosphine)palladium (308 mg, 0.28 mmol). Anhydrous toluene (15 mL) and tributylvinyltin (0.85 mL, 2.91 mmol) were added, and the reaction was heated to reflux under nitrogen for 16 h. The solution was cooled to RT and EtOAc (50 mL) was added. The mixture was washed with H2O (25 mL) and brine (25 mL), and dried over anhydrous MgSO4. The solvents were evaporated, and the resulting oil purified by flash chromatography over silica gel(0% to 25% EtOAc/hexanes) to provide 770 mg (78%) of [4-chloro-3-(3-cyano-5-vinyl-phenoxy)-2-fluoro-phenyl]-acetic acid ethyl ester (118).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]([F:41])([F:40])[C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:22][O:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.O>C1COCC1>[F:17][C:18]([F:40])([F:41])[C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:22][O:23][CH2:24][C:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
Ethyl diethoxyphosphorylacetate (30 mL, 150 mmol) was dropped into a suspension of sodium hydride (60% oily) (6.00 g, 150 mmol) in THF (300 mL) at room temperature during 30 minutes. After the dropping, the mixture was stirred at room temperature for 1 hour more, a solution of 2-(3,5-bis(trifluoromethyl)-benzyloxy)-1-phenylethanone (48.90 g, 135 mmol) in THF (100 mL) was dropped thereinto at room temperature during 30 minutes and the mixture was stirred for 1 hour more. The reaction mixture was added to water (1000 mL) followed by extracting with ethyl acetate. The organic layers were combined, washed with water and a saturated saline solution and dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residual oily product was purified by a silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give ethyl 4-(3,5-bis(trifluoromethyl)-benzyloxy)-3-phenyl-2-butenoate (40.00 g, 69%) as an oily product. 1H-NMR (DMSO-d6) δ: 1.23 (t, J=7.1 Hz, 3H), 4.15 (q, J=7.1 Hz, 2H), 4.63 (s, 2H), 5.08 (s, 2H), 6.24 (s, 1H), 7.39-7.43 (m, 3H), 7.57-7.61 (m, 2H), 7.79 (s, 2H), 7.96 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[CH:10]=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:2][CH3:3].ClS([N:25]=[C:26]=O)(=O)=O.CN(C)C=O.O>C(#N)C>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:17][CH2:16][C:8]2[C:9]3[C:10]([C:26]#[N:25])=[CH:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2c(ccc3[nH]ccc23)C1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CCCN(CCC)C1CCc2c(ccc3[nH]cc(C#N)c23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To an ice-cold solution of di-n-propyl-(6,7,8,9-tetrahydro-3H-benzo[e]indol-7yl)amine, 9a (Chart 2) (180 mg, 0.67 mmol) in acetonitrile (5 mL) was added dropwise with a solution of chlorosufonyl isocyanate (60 mL, 0.68 mmol) in acetonitrile (1 mL) over 10 minutes. After stirring for 1 hour, dimethyl formamide (100 mL) was added and the reaction was stirred for an additional 2 hours. Water was added and extraction (dichloromethane) followed by evaporation of the combined organic extracts afforded 170 mg (86%) of the crude product. Purification on a silica column (hexane/ethyl acetate/methanol) afforded 45 mg (23%) of the pure material.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:13]2[CH2:18][CH2:17][CH2:16][C:15]([OH:19])=[CH:14]2)=[CH:5][CH:4]=1
Reactant: O=C1CCCC(=O)C1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1=CC(=NNc2ccc(F)cc2)CCC1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A suspension of 4-fluorophenylhydrazine hydrochloride (50 g) in water (500 ml) was treated with sodium hydroxide (12.3 g) in water (50 ml) and the resultant solution added to solution of cyclohexane-1,3-dione (97%, 35.6 g) in water (300 ml) over 2 h under nitrogen with stirring. After a further 30 min, the precipitate was filtered off, washed with water (50 ml), air dried for 1 h, and dried in vacuo over phosphorus pentoxide at 75° to give the title compound as a powder (65.3 g) m.p. 175°-176°.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:37])[NH:25][CH2:26][CH2:27][CH:28]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)[CH3:29])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:37])[NH:25][CH2:26][CH2:27][CH:28]([N:30]1[CH2:35][CH2:34][CH:33]([NH:10][CH:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[CH2:8][NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:32][CH2:31]1)[CH3:29])([CH3:20])([CH3:21])[CH3:22]
Reactant: NC(CNC1CCCCC1)c1cc(F)ccc1F
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(=O)CC1
Product: CC(CCNC(=O)OC(C)(C)C)N1CCC(NC(CNC2CCCCC2)c2cc(F)ccc2F)CC1
Yield: 89.3 %

Procedure:
Using general procedure A, N2-cyclohexyl-1-(2,5-difluorophenyl)-ethane-1,2-diamine (750 mg, 2.95 mmol) and [3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (797 mg, 2.95 mmol) afforded {3-[4-(2-cyclohexylamino-1-{2,5-difluorophenyl}-ethylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (1.34 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][CH2:35][C:36]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2)=[O:37]
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-ethylphenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.327 mmol) in N,N-dimethylformamide (4.0 mL) was added chloroacetyl chloride (34 μL, 0.425 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-ethylphenyl]-3-(1-cyano-1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[C:16]([O:34][CH3:35])[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:37]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:42]=1>>[CH2:37]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[C:16]([O:34][CH3:35])[CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:42]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1CCN2S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CC3)cc1F

Procedure:
4-{[1-(3,5-Dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 539.26 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 4-{[1-(3,5-dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](N)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C(#N)C.N(OC(C)(C)C)=O.[BrH:27]>[Cu]Br>[Br:27][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:11][C:10]=1[CH2:12][CH3:13]
Reactant: Br
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1N
Agent: [Cu]Br
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: 25 °C

Procedure:
4′-Chloro-3-ethylbiphen-4-ylamine (14.3 g, 0.06 mol) is added to acetonitrile (143 ml) and stirred at room temperature until dissolution is complete. The reaction mixture is cooled to between −5° C. and 0° C., tert-butyl nitrite (90%, 9.8 ml, 0.074 mol) is added dropwise and the reaction mixture is maintained at between −5° C. and 0° C. for 30-40 minutes. The mixture is added slowly to a preheated (50° C.) suspension of copper (I) bromide (4.87 g, 0.034 mol) in hydrobromic acid (4.8 ml) and stirred at 50° C. for 10-15 minutes. The reaction mixture is cooled to room temperature, then poured into ice-cold water and extracted with ethyl acetate (3×500 ml). The organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to yield 4-bromo-4′-chloro-3-ethylbiphenyl (12 g).