Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O>CO>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH3:18])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH:27][CH2:34][C:30]2[NH:29][CH:33]=[CH:32][N:31]=2)=[CH:24][CH:25]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CN)cc1)C(=O)OC(C)(C)C
Reactant: O=Cc1ncc[nH]1
Solvent: CO
Product: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 107.5 %

Procedure:
The compound (0.78 g) obtained in Example 76-3 was dissolved in methanol (20 ml) and added with 2-imidazole carboxaldehyde (214.6 mg). The whole was stirred at room temperature for 17 hours. After the solvent was distilled off, the resultant was dried under vacuum, dissolved in methanol (15 ml), and added with sodium borohydride (217.8 mg) and the whole was stirred at room temperature for 45 minutes. The reaction solution was added with a saturated aqueous ammonium chloride solution (10 ml) and the whole was stirred at room temperature for 15 minutes. The reaction solution was added with a saturated saline solution and subjected to extraction with chloroform, followed by drying with anhydrous sodium sulfate. The solvent was distilled off. Then, the resultant residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.01 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]([CH3:16])[CH2:12][C:13](O)=[O:14])[N:10]=[C:6]2[C:5]([CH3:17])=[N:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]([CH3:16])[CH2:12][C:13]([Cl:21])=[O:14])[N:10]=[C:6]2[C:5]([CH3:17])=[N:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ncc(C)n2nc(C(C)CC(=O)O)nc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ncc(C)n2nc(C(C)CC(=O)Cl)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 3-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)butanoic acid (200 mg, 0.086 mmol) in DCM (15 mL) was added oxalyl chloride (3 mL) and DMF (0.1 mL). The mixture was stirred at room temperature for 2 h. The mixture was then evaporated under reduced pressure to give the product as a brown solid (208 mg, 96% yield).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Cl:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>>[Cl:9][C:10]1[CH:17]=[C:16]([O:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:8])[CH:1]=2)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: Cc1cccc(O)c1
Product: Cc1cccc(Oc2ccc(C=O)c(Cl)c2)c1

Procedure:
m-Cresol and 2-chloro-4-fluorobenzaldehyde were reacted according to the same experiment procedures as in Reference Example 1 of the pamphlet of WO 03029184 to obtain the target product as a colorless powder.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br-:19]>>[Br:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(=O)N(CCCCCO)C(C)C
Reactant: [Br-]
Product: CCCCCCC(=O)N(CCCCCBr)C(C)C
Yield: 82 %

Procedure:
N-(5-Hydroxypentyl)-N-isopropylheptanamide (0.25 g, 0.97 mmol) was converted to the corresponding bromide as described above to give the title compound (0.25 g. 82%) as a colorless oil. TLC:EtOAc/hexanes (3:7), Rf˜0.40; 1H NMR (300 MHz, 55/45 mixture of rotamers) δ 4.60-4.70 and 3.96-4.10 (m, 1H for two rotamers), 3.46 and 3.36 (t, J=5.8 Hz 2H for two rotamers), 3.02-3.10 (m, 2H), 2.30 and 2.22 (t, J=7.9 Hz, 2H for two rotamers), 1.80-1.97 (m, 2H), 1.40-1.70 (m, 6H), 1.20-1.40 (m, 6H), 1.16 and 1.10, (d, J=7.3 Hz, 6H for two rotamers), 0.86 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz) δ 172.79, 172.39, 48.17, 45.47, 43.32, 40.70, 33.89, 33.87, 33.49, 32.48, 32.30, 31.81, 31.78, 30.78, 29.27, 28.74, 26.05, 25.84, 25.69, 25.54, 22.64, 21.47, 20.62, 14.17. HRMS calcd for C15H31BrNO [M+1]+ 320.1589, found 320.1588.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9]C)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CCOCC>[OH:1][C:2]1[C:3]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([Cl:16])[CH:18]=1)=[O:9]
Reactant: COC(=O)c1sc2ccc(Cl)cc2c1O
Reactant: Nc1cccc(Cl)c1
Solvent: CCOCC
Product: O=C(Nc1cccc(Cl)c1)c1sc2ccc(Cl)cc2c1O
Temperature: 170 °C
Yield: 56.3 %

Procedure:
A mixture of methyl 3-hydroxy-5-chlorobenzo[b]thiophene-2-carboxylate (1.21 g; 0.005M) and 3-chloroaniline (1.28 g; 0.010M) is heated under a nitrogen atmosphere at 170° C. for 90 minutes. The reaction mixture was cooled to room temperature, taken up in 10 ml of ether, collected the solid, washed with 10 ml of ether, air dried, and recrystallized from ethyl acetate to give 0.95 g (56% yield) of the title compound as a light grey solid, m.p. 233°-235° C. (dec).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:29][CH:30]([CH2:32][OH:33])[CH3:31]>ClCCl>[OH:33][CH2:32][CH:30]([NH:29][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1)[CH3:31]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CC(N)CO
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CO)NC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
To a solution of 3-iodobenzoic acid (10.02 g, 40.30 mmol), in dry dichloromethane, at room temperature (180 mL) under a nitrogen atmosphere, EDCI (7.72 g, 40.30 mmol) was added followed by triethylamine (8.0 mL, 60.45 mmol) and the mixture was stirred at room temperature for further 5 minutes. DL Alaninol (3.02 g, 40.3 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organics were separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 1% to 8% methanol gradient) to afford compound 1 (4.14 g, 13.6 mmol, 34% yield) as an off white solid.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.FC(F)(F)C(O)=O.[CH:41]([O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][C:50](=[O:53])[CH:51]=[CH2:52])=[CH2:42]>>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH:41]([O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][C:50](=[O:53])[CH:51]=[CH2:52])[CH3:42])=[CH:4][CH:3]=1
Reactant: C=COCCOCCOC(=O)C=C
Reactant: O=c1c2ccccc2sc2c(O)ccc(F)c12
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)OCCOCCOC(C)Oc1ccc(F)c2c(=O)c3ccccc3sc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
1-fluoro-4-hydroxy-thioxanthen-9-one (2.5 g, 0.01 mol), 2,6-di-tert-butyl-4-methylphenol (0.07 g, 0.32 mmol) and trifluoroacetic acid (0.1 g=92.4 μL, 1.2 mmol) were added to 2-(2′-vinyloxyethoxy)ethylacrylate (27.6 g). The mixture was heated to 70° C. and stirred for 4 hours. After cooling down to room temperature, activated Lewatit M600 MB (10 g) was added and stirred for 1 hour. After filtration, a 15 w % solution of acrylic acid 2-{2-[1-(1-fluoro-9-oxo-9H-thioxanthen-4-yloxy)-ethoxy]-ethoxy}-ethyl ester in 2-(2′-vinyloxyethoxy)ethylacrylate was obtained, which was directly used in the radiation curable compositions according to a preferred embodiment of the present invention.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH3:17][O:18][CH2:19][CH2:20]O>>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:16][CH2:20][CH2:19][O:18][CH3:17])[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: COCCO
Reactant: CC(=O)Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Product: COCCOc1nc(NC(C)=O)nc2ccc(Cl)nc12
Yield: 13.5 %

Procedure:
5 mmol 2-acetamido-6-chloro-pyrido[3,2-d]pyrimidin-4(3H)-one (1.2 g) was reacted with 7.5 mmol 2-methoxyethanol (0.54 g) to give the pure title compound (0.2 g, yield: 14%) which was characterised as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]([C@H:28]([CH3:31])[CH2:29][OH:30])[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(O)C>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH2:18][CH2:19][N:20]([C@H:28]([CH3:31])[CH2:29][OH:30])[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1)CCN([C@H](C)CO)C2=O

Procedure:
A round bottom flask was charged with (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(2-(1-hydroxypropan-2-yl)-6-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)acetamide (50.0 mg, 0.000114 mol), ethanol (6 mL, 0.1 mol) and palladium, 10% weight on charcoal (1.4 mg, 0.000011 mol) was added and the flask was evacuated and flushes with hydrogen. The evacuation and flushing was repeated two times and the reaction was stirred under an atmosphere of hydrogen (balloon) over night. The reaction mixture was then filtered over cellite and solvent removed under reduced pressure. The residue was then purified by flash chromatography to get the product as white solid.
Reaction SMILES: [Li+].C[CH:3]([N-:5][CH:6](C)C)C.CNC.C[O:13][C:14]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1)=O>>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][N:19]=1)[C:14]([N:5]([CH3:6])[CH3:3])=[O:13]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CC(C)[N-]C(C)C
Agent: CNC
Agent: [Li+]
Product: CN(C)C(=O)c1ccnc(N)c1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To LDA (7.3 mL, 13 mmol, 1.8M in ether/heptane) at 0° C., add dropwise dimethylamine (13 mL, 26 mmol, 2M in THF) under nitrogen. Stir for 30 minutes and add 2-amino-4-pyridine carboxylic acid methyl ester (2 g, 13 mmol, in 3 mL of anhydrous THF and 2 mL of anhydrous ether). Seal and heat at 85° C. overnight. Cool the mixture to room temperature and quench with water. Dilute with EtOAc and isolate the top organic layer. Extract the aqueous layer further with saturated sodium bicarbonate and ether, then DCM. Pool all the organic layers, dry (MgSO4) and concentrate. Purify by strong cation exchange (SCX) column to obtain the crude product and use in the next step without further purification. LCMS (ES), m/z 166 (M+1).
Reaction SMILES: [F:1][C:2]1([F:26])[O:6][C:5]2[CH:7]=[C:8]([OH:25])[C:9]([C:11]3(O)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20]OC)[C:12]3=[O:23])=[CH:10][C:4]=2[O:3]1.FC1(F)OC2C=C(O)C(C3(O)C4C(=CC=CC=4)N(CC4OC(C(F)(F)F)=CC=4)C3=O)=CC=2O1>>[F:26][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]([OH:25])[C:9]([CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH3:20])[C:12]3=[O:23])=[CH:10][C:4]=2[O:3]1
Reactant: COCN1C(=O)C(O)(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc21
Agent: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc2c(cc1O)OC(F)(F)O2
Product: CN1C(=O)C(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 71B and making non-critical variations using 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-(methoxymethyl)-1,3-dihydro-2H-indol-2-one to replace 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one, 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-methyl-1,3-dihydro-2H-indol-2-one was obtained (85%) as a colorless amorphous solid: 1H NMR (300 MHz, CDCl3) δ7.47-7.40 (m, 1H), 7.37-7.31 (m, 1H), 7.28-7.20 (m, 2H), 6.99 (d, J=7.8 Hz, 1H), 6.85 (s, 1H), 6.60 (s, 1H), 5.10 (s, 1H), 3.25 (s, 3H); MS (ES+) m/z 320.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[CH:9][C:10]=1[NH:11][C:12]([O:14][CH2:15][C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][C:19]=2[CH:20]=1)=[O:13])=[O:4].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:25]1([C:22]2[CH:23]=[CH:24][C:18]3[O:17][C:16]([CH2:15][O:14][C:12]([NH:11][C:10]4[CH:9]=[CH:8][C:7]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:6][C:5]=4[C:3]([OH:4])=[O:2])=[O:13])=[CH:20][C:19]=3[CH:21]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(-c2ccccc2)ccc1NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(-c2ccccc2)cc1C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2o1
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a solution of 4-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-biphenyl-3-carboxylic acid methyl ester (1.04 g, 2.17 mmol) in THF (35 mL), methyl alcohol (4.5 mL) and water (5.5 mL) was added lithium hydroxide monohydrate (0.19 g, 4.47 mmol). The mixture was stirred for 3 h, and 1N HCl was added to adjust the pH to 2. The solvents were removed in vacuo and the resulting suspension was filtered. Recrystallisation of the white crude solid gave 0.54 g of 4-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-biphenyl-3-carboxylic acid 10, mp: 225.9-226.2° C.
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=2)=[C:10]([CH:51]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:50])[C:29]3[CH:34]=[C:33]([N+:35]([O-])=O)[CH:32]=[CH:31][C:30]=3[C:38]3[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=3)[CH2:24][CH2:23]2)[CH2:15][CH2:14]1)=[O:12])([O-])=O>[Pd].C(O)(=O)C.CO>[NH2:35][C:33]1[CH:32]=[CH:31][C:30]([C:38]2[CH:39]=[C:40]([O:48][CH3:49])[C:41]([O:46][CH3:47])=[C:42]([O:44][CH3:45])[CH:43]=2)=[C:29]([CH:34]=1)[C:28]([N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]3[CH:51]=[C:6]([NH2:3])[CH:7]=[CH:8][C:9]=3[C:52]3[CH:53]=[C:54]([O:62][CH3:63])[C:55]([O:60][CH3:61])=[C:56]([O:58][CH3:59])[CH:57]=3)[CH2:14][CH2:15]2)[CH2:23][CH2:24]1)=[O:50]
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cc2C(=O)N2CCN(CCCN3CCN(C(=O)c4cc([N+](=O)[O-])ccc4-c4cc(OC)c(OC)c(OC)c4)CC3)CC2)cc(OC)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(-c2ccc(N)cc2C(=O)N2CCN(CCCN3CCN(C(=O)c4cc(N)ccc4-c4cc(OC)c(OC)c(OC)c4)CC3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
10% Palladium on carbon (50 mg) was added to a solution in acetic acid-methanol (1 ml—1 ml) of 1,3-bis[4-[5-nitro-2-(3,4,5-trimethoxyphenyl)benzoyl]1-piperazinyl]propane dihydrochloride (91 mg; 0.10 mmol) synthesized by the process described in Example 8. After the mixture was stirred at room temperature for 3 hours under hydrogen, the catalyst was removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resultant concentrated residue to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 29 mg (yield: 37%) of 1,3-bis[4-[5-amino-2-(3,4,5-trimethoxyphenyl)benzoyl]-1-piperazinyl]propane as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[OH:26])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C@@H:25]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[OH:26])=[C:11]([C:43]3[CH2:44][CH2:45][O:40][CH2:41][CH:42]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(S(F)(F)(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(S(F)(F)(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (R)—((S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-yl)(4-(pentafluorosulfanyl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[O:34][C:35]([CH3:39])([CH3:38])[C:36]=1[CH3:37])#[N:31].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([CH3:38])([CH3:39])[O:34][C:33](=[C:40]([C:41]#[N:42])[C:43]#[N:44])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
In 6 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 250 mg (0.64 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 140 mg (0.70 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 49 mg of ammonium acetate, and the mixture was stirred at 70° C. for 4 hours. The solvent was evaporated off, and the residue was purified by silica gel column chromatography and washed with ethanol to give 205 mg of a black powder (yield: 56.2%; mp: 242-244° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26].N1C=CC=CC=1>C1C=CC=CC=1>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:26]
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (100 mg, 0.329 mmol) obtained in step C of Example 1-1 was dissolved in benzene (2 ml). Thereafter, chloroacetic acid chloride (29 μl, 0.362 mmol) and pyridine (80 μl, 0.986 mmol) were added to the solution, and the obtained mixture was stirred at a room temperature for 4 hours. Thereafter, the reaction solution was washed with 1 N hydrochloric acid, and was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was suspended in and washed with cold ethyl acetate, and a solid was collected by filtration, so as to obtain 2-chloro-N-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]acetamide (70 mg, 56%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([O:12][CH3:13])[CH:4]=1.S(Cl)(Cl)=O.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22]O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O.ClCCl.O>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:15])[F:14])[CH:11]=[CH:10][C:6]=1[C:7]1[O:9][CH2:22][C:21]([CH3:25])([CH3:24])[N:20]=1
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CC(C)(N)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 24.98 g (113 mmol) 4-(trifluoromethyl)-2-methoxy-benzoic acid in 220 ml toluene were added 82 ml (1.13 mol) thionyl chloride and 5 drops dimethylformamide. The mixture was heated to 80° C. for 3 h. Then the reaction mixture was concentrated at 50° C./10 mbar. The remaining acid chloride, 27.9 g of a light yellow liquid, was dissolved in 160 ml dichloromethane, cooled to 0° C. and a solution of 20.34 g (228 mmol) 2-amino-2-methyl-propan-1-ol in 60 ml dichloromethane added. The mixture was allowed to stir at ambient temperature for 16 h. The off-white suspension was diluted with water, the aqueous phase evaporated and the organic phase extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product, 33.2 g N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-4-trifluoro-methyl-benzamide, a light yellow oil was dissolved in 220 ml dichloromethane and cooled to 0° C. Then 24.7 ml (340 mmol) thionyl chloride was added drop-wise and the resulting light yellow solution stirred at ambient temperature for 16 h. Then the pH was adjusted to 10 by addition of saturated aqueous Na2CO3 solution. The aqueous layer was separated and extracted 3 times with tert-butyl methyl ether. The combined organic phases were washed twice with brine, dried over Na2SO4, filtered and concentrated to provide the title compound as light yellow oil which was used without further purification. MS (m/e): 274.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([O:22][C:23]2[S:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[N:27]=2)[CH:18]=[CH:19][C:20]=1[F:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClC(Cl)C>[F:14][C:15]1[CH:16]=[C:17]([O:22][C:23]2[S:24][C:25]([CH2:29][NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[CH2:10][C@H:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[C:26]([CH3:28])[N:27]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: Cc1nc(Oc2ccc(F)c(F)c2)sc1C=O
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1nc(Oc2ccc(F)c(F)c2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reaction time: 12 h
Yield: 65.6 %

Procedure:
To a mixture of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.054 g, 0.305 mmol) in dichloroethane (2 mL) was added 2-[(3,4-difluorophenyl)oxy]-4-methyl-1,3-thiazole-5-carbaldehyde (0.072 g, 0.282 mmol). The mixture was stirred for 12 h followed by addition of sodium triacetoxyborohydride (0.092 g, 0.434 mmol). The mixture was stirred for 5 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a yellow solid (0.077 g, 51%). 1H NMR (400 MHz, DMSO-d6): δ 7.59-7.47 (m, 2H), 7.18 (m, 1H), 6.87 (d, J=8.4 Hz, 2H), 6.51 (d, J=8.4 Hz, 2H), 4.23 (s, 2H), 2.47 (m, 1H), 2.17 (s, 3H), 1.59 (m, 1H), 1.29 (m, 1H), 1.18 (m, 1H). ES-MS m/z 416.98 (MH+).