Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:30]2[O:29][N:28]=[C:27]([CH3:26])[CH:31]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: Cc1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)no4)cc3)c2cc1C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) synthesized in Production Example 10 and phenyl N-(3-methylisoxazol-5-yl)carbamate (81 mg) were added to toluene (5 ml), then diisopropylethylamine (0.88 ml) was added and the mixture was heated and stirred at 100° C. for 2 hours. After cooling, the precipitated crystals were filtered and washed with an ethyl acetate:toluene (1:1) mixed solvent to obtain the title compound (102 mg).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37](I)[CH:36]=[CH:35][C:34]=3[O:40][CH3:41])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:42][O:43][C:44]([C:46]1[O:50][C:49](B(O)O)=[CH:48][CH:47]=1)=[O:45].N#N.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37]([C:49]4[O:50][C:46]([C:44]([O:43][CH3:42])=[O:45])=[CH:47][CH:48]=4)[CH:36]=[CH:35][C:34]=3[O:40][CH3:41])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(I)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)c1ccc(B(O)O)o1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(N4CCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4S,5R)-3-{[6-azetidin-1-yl-3-(5-iodo-2-methoxyphenyl)pyridin-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (20 mg, 0.029 mmol) and [5-(methoxycarbonyl)-2-furyl]boronic acid (14.75 mg, 0.087 mmol) in THF (0.5 mL) was degassed with N2 at 25° C. 1N K2CO3 (0.5 mL) was added followed by 1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.885 mg, 2.89 μmol) and the reaction was stirred vigorously at 25° C. under N2 overnight. The reaction was diluted with water and extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by preparative TLC (20×20, 1000 μm, hexanes/EtOAc (70/30)) to give methyl 5-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}-2-furoate. LCMS calc.=689.2. found=690.2 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H); 7.81-7.55 (m, 4H); 7.37 (d, J=8.3 Hz, 1H); 7.24 (d, J=3.7 Hz, 1H); 7.02 (d, J=8.6 Hz, 1H); 6.66 (s, 1H); 6.31 (d, J=8.3 Hz, 1H); 5.74-5.36 (m, 1H); 4.84 (d, J=16.1 Hz, 1H); 4.25 (s, 1H); 4.18-4.01 (m, 5H); 3.90 (s, 3H); 3.87 (s, 3H); 2.48-2.39 (m, 2H); 0.75-0.59 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:22][C:23]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([NH:18][C:19]2[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=2[F:36])[CH2:22][C:23]2([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(F)c(N)c2)CC1
Reactant: C[C@H](C(C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Product: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1F)c1ccc(Cl)cc1)C(F)(F)F

Procedure:
According to General Procedure 6, 1.2 g (4.5 mmol) of (2RS,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid and 1.3 g (4.95 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)-cyclopropanecarboxylate gave, after purification of the crude product by flash chromatography (silica gel; mobile phase cyclohexane/ethyl acetate 20:1), 1.6 g (69% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11]([CH:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[C:15]([O:17][CH3:18])=[O:16])(O)[CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][C:11](=[C:14]([C:19]3[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=3)[C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[CH:32][CH:31]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
A solution of 0.71 g (1.44 mmol) of methyl {1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}(3,5-difluorophenyl)acetate, 0.295 g (1.73 mmol) of methanesulfonyl anhydride, and 0.400 mL pyridine in 5 mL of dichloromethane was stirred at room temperature overnight. To this was added 0.400 mL of diazabicycloundecane and the solution remained stirring at room temperature. The mixture was partitioned between ether and water and the aqueous layer was washed with 20 mL of ether. The organic layers were washed with brine, combined, dried over MgSO4 and concentrated. The residue was filtered through a pad of silica gel using 20% ether-hexane to afford the title compound; 1NMR (CDCl3) δ 3.67 (s, 3H), 3.84 (m, 2H), 4.25 (m, 2H), 4.54 (s, 1H), 6.76 (m, 1H), 6.78 (m, 2H), 7.33 (m, 4H), 7.38 (m, 4H); Mass Spectrum: m/e=474 (M+1 35Cl, 35Cl) and 476 (M+1 35Cl, 37Cl).
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH2:10][NH+:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2].[I-].[C:29]([Mg]Br)#[C:30][CH3:31].O1CCCC1>C(OCC)C>[CH2:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([O:24][CH3:25])[C:9]=2[CH:10]([C:29]#[C:30][CH3:31])[N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]4[O:23][CH2:22][O:21][C:16]=4[CH:17]=3)[C:12]=12)[CH3:2]
Reactant: CC#C[Mg]Br
Reactant: CCC1=C2c3cc4c(cc3CC[NH+]2Cc2c1ccc(OC)c2OC)OCO4
Agent: [I-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC#CC1c2c(ccc(OC)c2OC)C(CC)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of 13-ethyl-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (200 mg, 0.4 mmol) in anhydrous diethyl ether (5 mL) at 0° C. was added a solution of 1-propynylmagnesium bromide solution in tetrahydrofuran (0.5 M, 8 mL, 4 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 13-ethyl-9,10-dimethoxy-8-prop-1-ynyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (130 mg, 80%). LC/MS m/e calcd for C25H25NO4 (M+H)+: 404.48, observed: 404.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.33 Hz, 3 H) 1.65 (d, J=2.02 Hz, 3 H) 2.60-2.81 (m, 4 H) 3.07 (m, 1 H) 3.18-3.25 (m, 1 H) 3.81 (d, J=8.84 Hz, 6 H) 5.32 (d, J=2.02 Hz, 1 H) 6.05 (d, J=6.32 Hz, 2 H) 6.86 (s, 1 H) 6.95 (s, 1 H) 6.96-7.02 (m, 2 H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([OH:11])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([OH:18])[N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:30][O:31][C:32]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)=[O:33]>O>[CH2:1]([C:5]1[N:10]([CH2:38][C:37]2[CH:36]=[CH:35][C:34]([C:32]([O:31][CH3:30])=[O:33])=[CH:41][CH:40]=2)[C:9](=[O:11])[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([OH:18])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(O)c(CC(=O)OCC)c(O)n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(O)c(CC(=O)OCC)c(=O)n1Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.8 %

Procedure:
100 mg of the product of Step D of Example 1 were introduced into 4 ml of dimethylformamide, 108 mg of potassium carbonate and 106 mg of [4-(methoxycarbonyl)-benzyl]-bromide. The mixture was stirred at ambient temperature for 6 hours, followed by pouring into water, extracting 3 times with ethyl acetate, washing with a saturated solution of sodium chloride and evaporating to dryness under reduced pressure. After chromatography on silica (eluant: methylene chloride-ethyl acetate: 6-4), 55 mg of the expected product melting at 170° C. were obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:13][C:12]1[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Clc1cccnc1Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1cccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A mixture of 2 g of pyrazole, 4.34 g of 2,3-dichloropyridine, 9.58 g of cesium carbonate and 40 ml N,N-dimethylformamide was stirred at 100° C. for 8 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto. The mixture was extracted with methyl tert-butyl ether three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3.57 g of 3-chloro-2-(1H-pyrazol-1-yl)pyridine of the formula:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH:18]([O:35]C(=O)CCl)[C:19](=[O:34])[NH:20][CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].NC(N)=S.C([O-])(O)=O.[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH:18]([OH:35])[C:19](=[O:34])[NH:20][CH2:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([O:30][CH3:31])=[CH:24][C:23]=1[O:32][CH3:33])[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(OC)c(CNC(=O)C(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(=O)CCl)c(OC)c1
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(OC)c(CNC(=O)C(O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)c1
Temperature: 50 °C

Procedure:
To a stirred solution of 9 (0.678 g, 1.18 mmol) in EtOH/THF (5/5 mL) was added thiourea (0.269 g, 3.54 mmol) and NaHCO3 (0.297 g, 3.54 mmol). The reaction mixture was stirred and heated to 50° C. for 1.5 h. The solvent was then removed under the reduced pressure and the residue was submitted to FC on silica gel (EtOAc/Hexanes, 45/55 to 60/40, V/V) to give 10 as a mixture of C(4) diastereomers as a waxy white solid (0.543 g, 91%): 1H NMR (200 MHz, CDCl3) δ 7.26 (br s, 1H), 6.13 (s, 1H), 6.12 (s, 1H), 5.45 (d, 1H, J=5.6 Hz), 4.63-4.03 (m, 5H), 3.82, 3.81 (s, s, total 9H), 2.43-1.84 (m, 2H), 1.45 (d, 9H, J=1.2 Hz), 1.43 (s, 9H); 13C NMR (50 MHz, CDCl3) δ 172.6, 172.0, 171.5, 171.3, 161.0, 159.5, 157.3, 156.1, 106.7, 90.8, 82.7, 82.4, 80.8, 80.3, 69.6, 68.5, 55.9, 55.4, 52.0, 51.0, 39.1, 38.5, 32.2, 31.9, 28.3, 28.0; HRMS calcd for C24H39N2O9 (M+H)+: 499.2656. found: 499.2669, 499.2662.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2)([O-])=O.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2Cc2cccnc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc2c(ccn2Cc2cccnc2)c1
Yield: 71.7 %

Procedure:
To a stirred suspension of nitroindole (D46) (0.63 g, 2.5 mmol), and iron powder (0.41 g, 7.2 mmol) in methanol (20 ml) was added a solution of ammonium chloride (0.66 g. 12.4 mmol) in water (13 ml). The mixture was then heated under reflux for 12 h, then filtered while hot and evaporate. The residue was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried and evaporated to give the title compound (0.40 g, 72%) as a gum.
Reaction SMILES: [C-]#N.[K+].[CH2:4]([N:6](CC)CC)C.[Cl:11][C:12]1[CH:21]=[CH:20][C:19]2[N+:18]([O-])=[CH:17][C:16]3[N:23]=[CH:24][N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[C:15]=3[C:14]=2[CH:13]=1>CN(C=O)C.C[Si](C)(C)Cl>[Cl:11][C:12]1[CH:21]=[CH:20][C:19]2[N:18]=[C:17]([C:4]#[N:6])[C:16]3[N:23]=[CH:24][N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[C:15]=3[C:14]=2[CH:13]=1
Reactant: [O-][n+]1cc2ncn(-c3ccccc3Cl)c2c2cc(Cl)ccc21
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1nc2ccc(Cl)cc2c2c1ncn2-c1ccccc1Cl
Temperature: 105 °C
Reaction time: 48 h

Procedure:
38.1 mg (0.5679 mmol) potassium cyanide and 239 μl (1.704 mmol) triethylamine (dry; Fluka) in 6 ml dry DMF, 182 μl trimethylchlorosilane (Fluka) are added within 10 min to a solution of 100 mg (0.30 mmol) of 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline 5-oxide (Example 71). The reaction mixture is stirred for 48 h at ca. 100-110° C. bath temperature. The cold solution is filtered, the solvent is evaporated. The residue is purified by chromatography on silica gel (CH2Cl2-methanol 9:1). The compound can be crystallized from CH2Cl2-hexane. mp: 248-250° C.; MS: 339 (M++1); HPLC: tret=13.19 min (Grad 1).
Reaction SMILES: O1CCN(C[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])CC1.C([O:23]C1C(C)=CC(C(O)=O)=CC=1C)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:8]([NH2:9])(=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Reactant: NC(CN1CCOCC1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-morpholino-1-phenylethanamine represented by Formula 113 (38.4 mg, 0.186 mmol) was slowly added to 4-benzyloxy-3,5-dimethylbenzoic acid represented by Formula 144 (52.5 mg, 0.205 mmol, purchased from Medizin Co. Ltd.) and diisopropylethylamine (0.13 mL, 0.745 mmol) in DMF (3 mL) solution at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 77.9 mg, 0.205 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (2 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate (K2CO3) solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was moved to a cartridge tube (6 mL, benzenesulfonic acid, 904030-WJ, UCT) using a small amount of ethyl acetate. Impurities were eliminated using methanol (15 mL) then separation and purification were conducted (using ethyl acetate/methanol/triethylamine, 20:2:1, v/v/v) to produce a benzamide compound represented by Formula 74 as a desired product (VVZ-080; 31 mg, 37% yield).
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]([S:18][C:19]2[CH:24]=[C:23]3[O:25][CH2:26][O:27][C:22]3=[CH:21][C:20]=2I)=[N:16][C:10]2[C:11]([NH2:15])=[N:12][CH:13]=[N:14][C:9]1=2)[CH3:3].C([N:36]1[CH:40]=[CH:39][CH2:38][CH2:37]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.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>[NH:36]1[CH2:40][CH:39]=[CH:38][CH:37]1[C:20]1[C:19]([S:18][C:17]2[N:8]([CH2:7][CH2:6][CH2:5][NH:4][CH:2]([CH3:3])[CH3:1])[C:9]3[C:10]([N:16]=2)=[C:11]([NH2:15])[N:12]=[CH:13][N:14]=3)=[CH:24][C:23]2[O:25][CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NCCCn1c(Sc2cc3c(cc2C2C=CCN2)OCO3)nc2c(N)ncnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
A solution of PU-H71 (30 mg, 0.0585 mmol) and N-Boc-2,3-dihydro-1H-pyrrole (19.8 mg, 20.2 μL, 0.117 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 μL, 0.117 mmol) and Pd(PPh3)4 (13.5 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 100° C. for 20 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 15:1) and the resulting residue was dissolved into 2 mL of CH2Cl2:TFA (4:1) and stirred for 1 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 10:1) to give 6.0 mg (23%) of DZ3-141. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.19 (s, 1H), 6.98 (s, 2H), 6.04 (m, 1H), 6.01 (s, 2H), 5.74 (m, 1H), 5.62 (d, J=2.0 Hz, 1H), 4.31 (t, J=6.9 Hz, 2H), 3.81-3.88 (m, 1H), 3.89-3.95 (m, 1H), 2.87 (septet, J=6.3 Hz, 1H), 2.68 (t, J=6.7 Hz, 2H), 2.14 (m, 2H), 1.15 (d, J=6.3 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C22H28N7O2S, 454.2025; found. 454.2046; HPLC: method A Rt=5.27, method B Rt=2.72.
Reaction SMILES: [C:1]1([B:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[B:26]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[OH:27])[OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]O>C(O)C>[C:1]1([B:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[B:26]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[O:27][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[O:12][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)CCO
Reactant: OB(c1ccccc1Oc1ccccc1B(O)c1cccc2ccccc12)c1cccc2ccccc12
Solvent: CCO
Product: CN(C)CCOB(c1ccccc1Oc1ccccc1B(OCCN(C)C)c1cccc2ccccc12)c1cccc2ccccc12

Procedure:
The entitled compound (32 mg) was obtained by allowing 86 mg of bis(4,4′-(naphthyl-hydroxyboryl)phenyl) ether and 31 mg of dimethylethanolamine to act in 0.25 mL of ethanol.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH2:14][O:15][C@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][C@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C:30](OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>CO>[F:12][C:10]([F:13])([F:11])[C:8]1[CH:7]=[C:6]([CH2:14][O:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH3:30])[C@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[C:4]([C:3]([F:28])([F:2])[F:29])[CH:9]=1
Reactant: CCOC(C)=O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from (+)-cis-3-((3,5 -bis(trifluoromethyl)phenyl)methyloxy )-2-phenylpiperidine hydrochloride (Example 5) by isolation of the free base (by extraction into ethyl acetate from 10% Na2CO3 solution) and alkylation using a procedure analogous to that described in Example 3, m.p.=40°-42° C.: [α]26D =+149° (c=0.56, MeOH); Found: C, 59.97; H, 4.95; N, 3.36. C21H21NOF6.0.1(H2O) requires C, 60.17; H, 5.10; N, 3.34%.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([C:13]2([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[C:7]1([C:13]2([NH:18][C:21](=[O:22])[C:20]([Cl:25])([Cl:24])[Cl:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC1(c2ccccc2)CCCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1(c2ccccc2)CCCC1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-phenylcyclopentylamine (8.1 g) and triethylamine (6.1 g), and trichloroacetyl chloride (9.1 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. The benzene layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 12.4 g g of N-(1-phenylcyclopentyl)trichloroacetamide. M.P., 114°-115.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([NH2:30])(=[O:29])=[O:28].[OH-].[Na+]>ClCCCl.C(N(CC)CC)C>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27]([NH:30][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9])(=[O:29])=[O:28]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: NS(=O)(=O)c1cccs1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NS(=O)(=O)c2cccs2)cn1
Temperature: 55 °C
Yield: 63.8 %

Procedure:
3.8 g of 1-methylpyrazole-4-carboxylic acid and 4.9 g of carbonyldiimidazole in 100 ml of 1,2-dichloroethane are heated at 55° C. for 3.5 h. 4.9 g of 2-thienylsulfonamide and 5.4 ml of triethylamine are added and then the mixture is heated at 55° C. for 13 h. After cooling, 40 ml of 10% strength aqueous NaOH solution are added and then the pH of the aqueous phase is adjusted to 1. The precipitate is removed and dried under reduced pressure. 5.2 g of N-(2-thienylsulfonyl)-1-methylpyrazole-4-carboxamide with a melting point of 174°-180° C. are obtained (active ingredient Example No. 103).
Reaction SMILES: [CH:1]1([CH2:4][C:5](F)(F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.BrCC1CC1.C(C1[S:28][CH2:27][CH2:26][CH2:25][S:24]1)(OCC)=O>>[CH:1]1([CH2:4][C:5]2([C:6]([O:8][CH2:9][CH3:10])=[O:7])[S:28][CH2:27][CH2:26][CH2:25][S:24]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1SCCCS1
Reactant: CCOC(=O)C(F)(F)CC1CC1
Agent: BrCC1CC1
Product: CCOC(=O)C1(CC2CC2)SCCCS1

Procedure:
A fifth aspect of this invention is a process for the preparation of ethyl 3-cyclopropyl-2,2-difluoropropanoate, which process comprises: (a) reacting bromomethylcyclopropane with 2-carboethoxy-1,3-dithiane in the presence of strong base to give ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate; (b) reacting the ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate with N-bromosuccinimide to give ethyl 3-cyclopropyl-2-oxopropanoate; and (c) reacting the ethyl 3-cyclopropyl-2-oxopropanoate with a fluorinating agent.