Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(O)C.Cl.[CH3:16][NH:17][CH3:18]>C(N(CC)CC)C>[CH3:16][N:17]([CH3:18])[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: CNC
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 130 °C
Reaction time: 20 h
Yield: 17390.1 %

Procedure:
5-Chloro-2-nitroaniline (50 g; 0.29 mol) was added to a 5 L bomb followed by ethanol (1.1 L) at 0-5° C. Dimethylamine hydrochloride (130 g; 1.59 mmol) was added in one portion followed by triethylamine (260 ml) and the bomb quickly sealed. The bomb was heated to 130° C. with stirring at 4 bar for 20 hours. The reaction mixture was then allowed to cool to room temperature and the ethanol was removed under vacuum. 2 M sodium hydroxide solution (1 L) was added to the crude residue and this was extracted with ethyl acetate (1×1.3 L then 2×500 ml). The combined organic layers were washed with brine (150 ml), dried (magnesium sulphate), filtered and evaporated to give the 5-dimethylamino-2-nitroaniline (50.1 g, 96%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH3:36][C:37](O)([C:39]([CH3:42])([OH:41])[CH3:40])[CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][C:32]2([O:41][C:39]([CH3:42])([CH3:40])[C:37]([CH3:38])([CH3:36])[O:35]2)[CH2:33][CH2:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CC(C)(O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OC(C)(C)C(C)(C)O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 139.9 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g), 2,3-dimethylbutane-2,3-diol (0.57 g), p-toluenesulfonic acid monohydrate (0.061 g) and toluene (30 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.85 g, 47%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[C:17]12([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>C(O)CCC>[C:17]12([C:27]([N:29]3[CH2:34][CH2:33][N:32]([C:2]4[N:11]=[C:10]([NH2:12])[C:9]5[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=5)[N:3]=4)[CH2:31][CH2:30]3)=[O:28])[CH2:18][CH:19]3[CH2:20][CH:21]([CH2:22][CH:23]([CH2:25]3)[CH2:24]1)[CH2:26]2
Reactant: O=C(N1CCNCC1)C12CC3CC(CC(C3)C1)C2
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(C(=O)C45CC6CC(CC(C6)C4)C5)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 2-chloro-4-amino-6,7-dimethoxyquinazoline (2.4 g), 1-(1-adamantanecarbonyl)piperazine (2.5 g) and n-butanol (60 ml) was refluxed for 10 hours. After cooling, the solvent was evaporated under reduced pressure, and water was added to the residue. After treating with aqueous ammonia, the precipitated crystals were collected to give crude 2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazoline, m.p. 237°-240° C. Recrystallization from methanol gave pure 2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazoline, m.p. 242°-243° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([C:15]#[C:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5]2)[CH2:3][CH2:2]1.[H][H]>CN(C)C=O.C(O)(=O)C.[Pd]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:36])=[C:11]([CH2:15][CH2:16][C:17]4[CH:22]=[C:21]([CH2:23][C:24]5[C:25]([NH2:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=5)[CH:20]=[C:19]([O:32][CH3:33])[C:18]=4[O:34][CH3:35])[C:12]=3[F:14])[C:7](=[O:37])[C:6]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(CCc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)c(F)cc2c1=O
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A suspension of 342 mg of ethyl 1-cyclopropyl-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 12a)) and 70 mg of 10% palladium-on-charcoal in 35 ml of dimethylformamide and 35 ml of acetic acid is hydrogenated at normal hydrogen pressure. After 6 hrs. the reaction mixture is filtered and the filtrate is concentrated in a high vacuum at 50°. The yellow residue is treated with 100 ml of 1N aqueous sodium hydroxide solution and extracted three times with 50 ml of methylene chloride each time. The combined organic phases are washed with 50 ml of water, dried over magnesium sulphate and concentrated. The crude product is triturated with 10 ml of hot ethyl acetate and filtered off under suction. 275 mg (80%) of ethyl 1-cyclopropyl-7-[2-[5-(2,4-diamino-pyrimidin-5-yl-methyl)-2,3-dimethoxy-phenyl]ethyl]-6,8-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate are obtained as a yellowish solid. M.p. 218°-220°.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:68](O)=[O:69])[C@H:64]([CH2:66][CH3:67])[CH3:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:68]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:69])[C@H:64]([CH2:66][CH3:67])[CH3:65]
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.1 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (250 mg, 0.65 mmol), DCC (160 mg, 0.78 mmol) and DMAP (8 mg, 0.06 mmol) in ethyl acetate (15 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-isoleucine (228 mg, 0.65 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (275 mg) was dissolved in dry THF (10 mL) and cooled to 0° C. Dimethylamine (10 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 110 mg (31%) of the title compound as an off white solid.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[C:9]([CH3:23])([CH3:22])[C:10]([NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[O:15][N:14]=1)=[O:11]>C1COCC1>[CH2:1]([NH:5][C:9]([CH3:23])([CH3:22])[C:10]([NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[O:15][N:14]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCNC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 16 h
Yield: 35.9 %

Procedure:
To a solution of n-butylamine (51 mg, 0.69 mmol) in THF (2 mL) at room temperature under nitrogen is added NaH (33 mg, 1.38 mmol) in portions over 10 min. After the addition is complete, 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide (0.10 g, 0.35 mmol) is introduced to the reaction and the resulting mixture is stirred for 16 h. The solvent is then removed under reduced pressure and the residue is partitioned between DCM and saturated aqueous NaHCO3 solution. The organic phase is separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product is purified by mass-triggered preparative HPLC. The purified compound is dissolved in DCM and free-based with Ambersep 900-OH resin over 2 h. After this time, the suspension is filtered and the filtrate is concentrated under reduced pressure to provide the title compound (35.4 mg, 37%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.[Cl:50][C:51]1[CH:60]=[CH:59][C:54]2[N:55]=[C:56]([SH:58])[NH:57][C:53]=2[CH:52]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:50][C:51]1[CH:60]=[CH:59][C:54]2[NH:55][C:56]([S:58][C:2]3[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([Cl:26])[CH:17]=4)([CH:9]4[CH2:10][CH2:11][CH2:12][CH2:13]4)[CH2:6][C:7]=3[OH:8])=[N:57][C:53]=2[CH:52]=1
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1nc2ccc(Cl)cc2[nH]1
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-benzimidazole-2-thiol was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 1.34 (d, J=6.1 Hz, 6H), 1.41-1.82 (m, 10H), 2.07-2.14 (m, 1H), 2.55-2.88 (m, 4H), 3.4 (brs, 1H), 4.44-4.48 (m, 1H), 6.81-6.91 (m, 2H), 7.13-7.39 (m, 4H), 12.0 (brs, 1H); ESIMS (MH+) (C28H30Cl2N2O4S): 562.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:13][CH2:14][Mg+].[Br-].ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.CCOC(C)=O>C1COCC1>[CH2:13]([C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: CC[Mg+]
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: -15 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
To a solution of 5-nitrobenzimidazole (2.8 g, 17 mmol) in THF was added 16 ml of EtMgBr solution (48 mmol) and reaction mixture was stirred for 2 h at −15° C. A solution of tetrachloro-1,4-benzoquinone (8.8 g, 36 mmol) in THF was added dropwise into reaction mixture, which was allowed to warm up to 25° C. over 1 h. Silica gel (20 g) was added into reaction mixture and solvent was removed in vacuo to provide a brown silica gel powder which was subjected to column chromatography (EtOAc, neat) to provide 1.7 g (8.9 mmol, 52%) of 4-ethyl-5-nitrobenzimidazole, which was subsequently subjected to hydrogenation (H2, Pd/C) to yield 1.32 g (8.2 mmol) of 4-ethyl-5-aminobenzimidazole.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)=[O:8].I[C:19]1[C:27]2[C:22](=[N:23][CH:24]=[N:25][C:26]=2[NH2:28])[N:21]([CH:29]([CH3:31])[CH3:30])[N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[N:21]([CH:29]([CH3:31])[CH3:30])[N:20]=[C:19]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:2]3[S:1][CH2:5][CH2:4][N:3]=3)=[O:8])[C:27]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: O=C(NC1=NCCS1)c1cccc(B(O)O)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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccc(C(=O)NC3=NCCS3)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 66.7 %

Procedure:
A solution of [3-((4,5-dihydrothiazol-2-yl)carbamoyl)phenyl]boronic acid (19 mg, 0.08 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA30 (17.8 mg, 67% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1
Reactant: O=c1ncc(F)c[nH]1
Reactant: O=C(CBr)c1cccs1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(F)cnc1=O)c1cccs1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
A mixture of 5-fluoropyrimidin-2-one (456 mg) and 2-bromoacetylthiophene (820 mg) in triethylamine (1.33 ml) and ethanol (25 ml) was stirred at room temperature. After 2.5 h. the reaction mixture was concentrated to ca. 5 ml, diluted with ethyl acetate (300 ml) washed with water (3×50 ml), dried (MgSO4) and evaporated to a foam. This was crystallised from acetone to give the title pyrimidinone (225 mg), m.p. 183°-190° C. (dec) λmax (EtOH) 260 nm (ε10,308), 285.5 nm (ε 8,430).
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:14][CH:15]=1.C(N(CC)CC)C.[H][H]>C(O)(C)C>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]=2)=[N:14][CH:15]=1
Reactant: [H][H]
Reactant: Cc1ccc(-c2ccncc2)nc1
Agent: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(C2=CCNCC2)nc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 40.1 %

Procedure:
Benzyl bromide in an amount of 10.5 g was added to a solution of 10 g of 5-methyl-2,4′-bipyridine in 70 mL of isopropyl alcohol, and stirred for 5 hours at 50° C. To the resulting reaction solution, 1.0 g of 2% palladium-S carbon and 6.0 g of triethylamine were added. This admixture was put in an autoclave, the autoclave's atmosphere was replaced twice with nitrogen gas under a nitrogen pressure of 196 kPa, and then hydrogen gas was blown into the autoclave over 3 hours at 80° C. under a hydrogen pressure of 196 kPa until the absorption of hydrogen gas in a volume of 4,200 mL was completed. After the replacement with nitrogen, the catalyst was filtered out and the resulting filtrate was concentrated under a reduced pressure of 1.33 kPa until the quantity thereof was reduced to 18.0 g. Further thereto, 50 mL of water and 10 g of a 25% aqueous solution of sodium hydroxide were added. The resulting solution was extracted with three 200 mL portions of ethyl acetate, and the organic layer was concentrated. The thus obtained solid was adsorbed to NH2-modified silica gel (produced by Biotage Japan, Ltd.), and eluted with ethylacetate. The fraction obtained was concentrated, and the crystals thus deposited were dried to give 4.1 g of the intended compound as light yellow crystals. Yield rate: 40%, EI-MS: (m/z) 174 (M+), melting point: 78-80° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[Mg].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16](Br)[CH:17]=[CH:18][CH:19]=1.[Cl-].[NH4+]>CCOCC>[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[C:1]([CH2:2][CH3:3])([OH:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccccc1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)(c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 37.5 g. of propiophenone in 200 ml. of dry ether is added dropwise to a -10° C. Grignard solution prepared from 13.6 g. of magnesium turnings and 126 g. of 3-trifluoromethyl-bromobenzene in 182 ml. of dry ether. The reaction mixture is stirred at 0° C. for 30 minutes, thereafter refluxed for 1 hour. The mixture is cooled to 0° C., and the Grignard complex is decomposed with a 10% aqueous ammonium chloride solution. The etheral phase is separated, washed until neutral, and dried over anhydrous sodium sulfate. The solvent is evaporated, and the residual oil is subjected to fractional distillation in vacuo. This way 57.3 g. of 3-trifluoromethyl-α-ethyl-benzhydrol are obtained; b.p.: 106°-108° C./0.03 mmHg.
Reaction SMILES: [NH2:1][C:2]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][C:2]([NH:1][C:37](=[O:39])[CH3:38])([CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CCC(N)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
To 5 ml CH2Cl2 was added 1 g of triester 62 (2.4 mmol, 1 equiv) and 0.3 g triethylamine (2.9 mmol, 1.2 equiv.) The solution was cooled to 0° C. with an ice bath and 0.23 g acetyl chloride (2.9 mmol, 1.2 equiv) was added dropwise. The solution was stirred for a further 4 hours and allowed to warm slowly to room temperature. The solution was poured into a separating funnel and washed with 2×15 ml HCl (5% aqueous) and 1×15 ml concentrated NaCl. The solution was dried over Na2SO4 and the solvent was removed in vacuo. The residue was dissolved in minimal EtOAc and loaded onto a silica column, where it was purified by column chromatography with EtOAc and hexane (1:1) to give 0.79 g of a white solid in 72% yield.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([NH2:19])=[C:14]([NH2:20])[CH:13]=1>>[F:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][C:17]=1[F:18])[NH:19][C:1](=[O:8])[C:2](=[O:4])[NH:20]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)c(F)cc1N
Product: O=c1[nH]c2cc(F)c(F)cc2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound (Sarges, R. et al., J. Med. Chem. 33:2240 (1990)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (1.11 g, 7.63 mmol and 4,5-difluoro-1,2-diaminobenzene (110 mg, 0.763 mmol) was heated to reflux under N2 for 2 h. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with hexanes and air dried. This ;gray brown solid was recrystallized from 20 ml of EtOH and the brown-white crystals collected by vacuum filtration and the crystals further dried under vacuum (0.5 torr, 25° C.) to yield 45.3 mg (30.0%) mp>360° C. (lit.>310° C.). 1H NMR (d6 -acetone) δ7.19 (t, 2H, ArH, JH-F =9.3), 10.9 (br s, 2H, NH).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[N:55]=[C:54]([CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[O:53][N:52]=2)=[CH:47][CH:46]=1)(=[O:44])=[O:43]>CN(C=O)C>[F:9][C:2]([F:1])([F:10])[CH2:3][CH2:4][CH2:5][C:6]([N:59]1[CH2:58][CH2:57][CH:56]([C:54]2[O:53][N:52]=[C:51]([C:48]3[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:43])=[O:44])=[CH:46][CH:47]=3)[N:55]=2)[CH2:61][CH2:60]1)=[O:8]
Reactant: CS(=O)(=O)c1ccc(-c2noc(C3CCNCC3)n2)cc1
Reactant: O=C(O)CCCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-c2noc(C3CCN(C(=O)CCCC(F)(F)F)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
5,5,5-Trifluoropentanoic acid (1.3 equiv), EDCI (1.3 equiv), HOBt (0.3 equiv) and diisopropylethylamine (4 equiv) were mixed in DMF (2 mL) for 5 minutes. 4-(3-[4-(methylsulfonyl)phenyl-]1,2,4-oxadiazol-5-yl]piperidine (34c) (0.85 mmol, 1 equiv) was added with 3 mL of DMF. The reaction mixture was stirred overnight at room temperature and then evaporated under reduced pressure and purified by preparative HPLC. Yield 69%; 1H NMR (CD2Cl2) δ 8.32 (d, J=8.7 Hz, 2H), 8.08 (d, J=8.7 Hz, 2H), 4.52-4.57 (m, 1H), 3.92-3.96 (m, 1H), 3.23-3.39 (m, 2H), 3.11 (s, 3H), 2.92-3.01 (m, 1H), 2.46 (t, J=7.2 Hz, 2H), 2.16-2.32 (m, 4H), 1.82-2.01 (m, 4H). tR LCMS 5.7 min. Purity >99%; MS [M+H]+ m/z 446.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][Cl:19])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>[Pt]=S.[C].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][Cl:19]
Reactant: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: S=[Pt]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCl)cc1N
Temperature: 50 °C
Yield: 101.6 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 1.02 g (3.45 mmol) of methyl 5-methoxy-4-(2-chloroethoxy)-2-nitrobenzoate (purity: 98%) obtained in Reference Example III-2 and 20 mL of methanol. The resulting mixture was heated to 50° C. under stirring. To the mixture was added 0.5 g of 3 wt. % platinum sulfide/carbon (containing 65.7% water) at the same temperature. The resulting mixture was heated to the same temperature for one hour, while hydrogen was introduced to the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 0.91 g (isolated yield: 93.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(2-chloroethoxy)-anthranilate as a white crystalline product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1F.[CH3:13][O-:14].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[O:14][CH3:13]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,2,4-Trifluoro-5-nitrobenzene (10 g, 56.5 mmol) was dissolved in methanol, cooled in ice and treated with 25% sodium methoxide in methanol. After being stirred at room temperature for 6 hours the mixture was diluted with water and extracted with ethyl acetate to give 1,4-difluoro-2-methoxy-5-nitrobenzene (10.1 g). This was dissolved in ethanol (400 ml) and hydrogenated over 10% palladium on carbon to give the title compound (7.8 g).