Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1[C:6](=[O:17])[O:7][C:8]([CH2:15][CH3:16])=[C:9](C(O)=O)[C:10]=1[OH:11])(=O)CC>S(=O)(=O)(O)O.O>[OH:11][C:10]1[CH:9]=[C:8]([CH2:15][CH3:16])[O:7][C:6](=[O:17])[CH:5]=1
Reactant: CCC(=O)c1c(O)c(C(=O)O)c(CC)oc1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1cc(O)cc(=O)o1
Reaction time: 2 h

Procedure:
A solution of 3-propionyl-4-hydroxy-5-carboxy-6-ethyl-2-pyrone (7 gm) in concentrated sulphuric acid (14 ml) and water (2 ml) was heated in an oil bath set at 120° C. for 2 hours. The solution was cooled and then poured into ice. The insoluble solid was filtered. The filtrate was extracted with ethyl acetate (3×100 ml). The combined organic layer was dried over magnesium sulphate and evaporated to give a dirty brown solid. The combined solid from the filtration and the extraction was purified by flash column chromatography (Whatman LPS-II silica gel, elution gradient: 40 to 80% ethyl acetate:pet. ether 30-60) to give 4-hydroxy-6-ethyl-2-pyrone, which was further purified by recrystallization from ether. (Yield: 2.7 gm), m.p. 106°-108° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:56])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([N:34]3[CH2:38][CH2:37][CH2:36][C@H:35]3[C:39]([O:41]CC3C=CC=CC=3)=[O:40])=[O:33])[N:27]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[CH:50]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:56])[C@@H:13]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([O:30][CH2:31][C:32]([N:34]3[CH2:38][CH2:37][CH2:36][C@H:35]3[C:39]([OH:41])=[O:40])=[O:33])[N:27]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[CH:50]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)O)n(-c3cccc(F)c3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 2.50 g 4-((S)-2-{[5-[2-((S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-(3-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 25 ml ethyl acetate were added under argon 0.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 24 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 2.06 g colorless foam.
Reaction SMILES: [C:1](=[NH:5])(OC)[CH3:2].[NH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:22])=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[NH:9][N:8]=1>C(#N)C.C(O)(=O)C>[Cl:22][C:12]1[CH:11]=[C:10]2[C:15]([C:7]([NH:6][C:1](=[NH:5])[CH3:2])=[N:8][NH:9]2)=[CH:14][C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(C)=N
Reactant: Nc1n[nH]c2cc(Cl)c(-c3ccccc3)cc12
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=N)Nc1n[nH]c2cc(Cl)c(-c3ccccc3)cc12
Reaction time: 0.08 h

Procedure:
33 mg of methyl acetimidate are added to 50 mg of 3-amino-6-chloro-5-phenyl-1H-indazole in 3 ml of acetonitrile and 12 mg of acetic acid. The reaction is placed under microwave radiation at 180° C. for 5 min. After the usual treatments and purification through silica, 35 mg of N-(6-chloro-5-phenyl-1H-indazol-3-yl)acetamidine are obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].CO.[H][H]>[Pd].C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:36])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=1)([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: CCCCCCCCC1(COc2ccc(N)cc2)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1

Procedure:
Using Paar's hydrogenation apparatus, a mixture of 4 g of 6-acetoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman (prepared as described in Preparation 16), 0.8 g of 10% w/w palladium-on-carbon, 30 ml of methanol and 10 ml of benzene was stirred for 5 hours under 3-5 atmospheres (about 3-5 bars) pressure or hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure. The crystals thus obtained were washed with hexane to give the title compound, melting at 112°-114° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][C:4]1[N:3]=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:25])([F:24])[F:13])[N:7]=[C:6]([NH2:8])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc(N)c1[N+](=O)[O-]

Procedure:
To a solution of 2-chloro-6-methyl-5-nitro-pyrimidin-4-ylamine (920 mg, 4.89 mmol) in 1,4-dioxane (50 mL) was treated with (2-trifluoromethylphenyl)boronic acid (1.3 g, 6.8 mmol), K3PO4 (2.07 g, 9.78 mmol), and (dppf)PdCl2.DCM (318 mg, 0.487 mmol) was heated to 100° C. for 4 h under Ar. The cooled mixture was filtered through a pad of diatomaceous earth, diluted with water, and extracted thrice with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica (0:100 v/v to 100:0 v/v EtOAc-hexanes over 20 min) to yield 6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-ylamine. 1H-NMR (400 MHz, CDCl3) δ: 7.80 (d, J=7.6 Hz, 1H), 7.71-7.75 (m, 1H), 7.65 (t, J=6.9 Hz, 1H), 7.57-7.62 (m, 1H), 2.84 (s, 3H).
Reaction SMILES: C=O.[CH2:3]([O:5][C:6](=[O:26])[CH:7]([CH:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH3:12])[C:8](O)=O)[CH3:4].C(NCC)C.CCOC(C)=O>C(Cl)Cl>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH:11]([CH3:12])[C:7]([C:6]([O:5][CH2:3][CH3:4])=[O:26])=[CH2:8])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)C(C(=O)O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: ClCCl
Product: C=C(C(=O)OCC)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Formaldehyde (132 mg, 1.65 mmol, 37% in water) was added to a solution of of crude 2-[1-(1-tert-butoxycarbonyl-piperidin4-yl)-ethyl]-malonic acid monoethyl ester (416 mg) in methylene chloride (2 mL) at 0° C. Diethylamine (153 μL, 1.47 mmol) was added dropwise and the mixture was stirred at room temperature over night. EtOAc was added and the mixture was washed with water and saturated NaHCO3, dried and concentrated under reduced pressure. The crude was purified by flash chromatography (toluene/EtOAc, 3:1) to give 4-(2-ethoxycarbonyl-1-methyl-allyl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 49% over two steps).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[N:3]1[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:56]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)(=[O:58])[CH3:57]>CN(C)C(=O)C>[C:56]([N:59]1[CH2:64][CH2:63][N:62]([C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([CH2:13][N:3]3[C:4](=[O:12])[CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]3=[O:1])[CH2:15][CH2:16]2)=[O:22])[CH2:61][CH2:60]1)(=[O:58])[CH3:57]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C1Cc2ccccc2C(=O)N1C[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)[C@H]2CC[C@H](CN3C(=O)Cc4ccccc4C3=O)CC2)CC1
Reaction time: 1 h

Procedure:
trans-4-(1,3-Dioxo-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-cyclo hexanecarboxylic acid (100 mg, 0.33 mmol) was dissolved in N,N-dimethyl acetamide (3 mL), HATU (125 mg, 0.33 mmol) and diisopropyl ethylamine (0.06 mL, 0.33 mmol) were added and the mixture was left stirring for 1 h. Then 1-acetylpiperazine (128 mg, 0.3 mmol) was added and the reaction stirred for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in 2 mL of DCM and washed with 2 mL of 0.4M Na2CO3 solution. The organic phase was collected and the solvent removed under reduced pressure. The crude was purified by SiO2 column, eluting with DCM-MeOH (97:3) and the fractions containing the desired product collected and further purified by prep HPLC. 42 mg of the title product were obtained (31% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:13])[C:9]#[N:10])[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: N#CCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
(5-Bromo-pyridin-3-yl)-acetonitrile (1.0 g, 0.005 mol) and 60% NaH (0.780 g) are mixed in DMF (25 mL) at 0° C. and stirred at room temperature for 1 h. MeI (1.2 ml) is added to this mixture at 0° C. and stirred at room temperature overnight. 2-(5-bromo-pyridin-3-yl)-propionitrile is obtained by prep-HPLC (0.3 g, 28% yield).
Reaction SMILES: C(OC(Cl)=O)(C)C.[Cl:8][C:9]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12][C:13]([OH:15])=O.CN1CCOCC1.[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:35]=[CH:34][C:33]=1[NH2:46]>C1COCC1>[Cl:31][C:32]1[CH:37]=[C:36]([O:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:35]=[CH:34][C:33]=1[NH:46][C:13](=[O:15])[CH2:12][O:11][C:10]1[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:9]=1[Cl:8]
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)c(Cl)c1
Agent: CC(C)OC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.141 mL (1.080 mmol) chloroformic acid-isopropylester was added dropwise at −10° C. to a solution of 0.254 g (0.982 mmol) (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 0.119 mL (1.080 mmol) N-methylmorpholine in 20 mL abs. THF and the mixture was stirred for a further 10 min. 0.250 g (1.031 mmol) 2-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z27b) was added, the mixture was stirred for 1 h at RT and then evaporated down i. vac. Water was added and the aqueous phase was exhaustively extracted with dichloromethane. The combined org. phases were dried over sodium sulphate, evaporated down i. vac. and the residue stirred with ether. The precipitate was filtered off, washed with ether and dried in a HV.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[CH3:11][N:12](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[NH2:7][C:6]1[CH:8]=[C:2]([Br:1])[C:3]([CH3:10])=[CH:4][C:5]=1[C:11]#[N:12]
Reactant: Cc1cc(I)c(N)cc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)c(N)cc1Br
Temperature: 90 °C
Yield: 83 %

Procedure:
A mixture of 5-bromo-2-iodo-4-methylaniline (5.25 g, 16.8 mmol) and zinc cyanide (0.988 g, 8.41 mmol) in DMF (80 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with tetrakis(triphenylphosphine)palladium (0.972 g, 0.841 mmol) and heated at 90° C. overnight. The cooled mixture was diluted with EtOAc and washed sequentially with 10% aqueous LiCl (twice) and brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 1%, 2.5%, 5% and 50%), to give a brown solid. The residue was further purified by trituration with MeOH to give three crops of solid. The filtrate was again purified by column chromatography on silica gel, eluting with EtOAc-hexanes (5%, then 10%). The resulting solid was combined with the other crops to provide 2-amino-4-bromo-5-methylbenzonitrile as a tan solid (2.95 g, 83% yield). Mass spectrum m/z 211, 213 (M+H)+.
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:29]1[CH:35]=[CH:34][C:33]2[CH:36]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=[CH:39][C:32]=2[O:31][CH2:30]1.Cl>O1CCCC1.ClCCl.O>[Cl:7][CH:8]=[C:29]1[CH:35]=[CH:34][C:33]2[CH:36]=[C:37]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=[CH:39][C:32]=2[O:31][CH2:30]1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C=CC(=O)CO2
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
1.3 equivalents of n-butyllithium are added to a suspension of 122 mg (0.35 mmol) of chloromethyltriphenylphosphonium chloride in tetrahydrofuran cooled to 0° C. After stirring for one hour, the ylide is added at 0° C., via a hollow tube, to 55 mg (0.25 mmol) of methyl 3-oxo-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 31. Immediately afterwards, water, 1N hydrochloric acid and dichloromethane are added. The phases are separated and then the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, are then dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 5/95) to provide 61 mg (96%) of methyl 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carboxylate in the form of a yellow-white solid comprising two Z/E isomers as a mixture in an 85/15 ratio; M.p.=72–77° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[C:4]([CH3:22])[CH:3]=1.[C-:23]#[N:24].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:23]#[N:24])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[C:4]([CH3:22])[CH:3]=1
Reactant: [C-]#N
Reactant: Cc1cc(Br)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C)c1NC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
To a solution of N-(4-bromo-2,6-dimethyl-phenyl)-4-fluoro-3-nitro-benzamide (18.3 g, 49.8 mmol) (Example I1) in N,N-dimethylformamide (115 ml) was added sodium cyanide (2.7 g, 54.8 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, then heated to 60° C. for 16 hours. More sodium cyanide (0.73 g, 14.8 mmol) was added and the reaction mixture was heated to 60° C. for a further 8 hours. The reaction mixture was cooled to ambient temperature before the addition of water (200 ml) and ethyl acetate (100 ml). The organic extract was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1), yielding N-(4-bromo-2,6-dimethyl-phenyl)-4-cyano-3-nitro-benzamide (11.8 g, 63% yield). LC/MS (Method A): 374 (MH+). 1H-NMR (400 MHz, DMSO-d6): 8.91 (s, 1H), 8.53 (d, 1H), 8.4 (d, 1H), 7.4 (s, 2H), 2.2 (s, 6H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cc1
Yield: 105.5 %

Procedure:
Pyrrolidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (116.8 mg) was dissolved in tetrahydrofuran (3 ml), 20% palladium hydroxide on carbon (25.0 mg) was added under a nitrogen atmosphere at room temperature while stirring, followed by stirring under a hydrogen atmosphere for 7 hr. The atmosphere in the reaction vessel was replaced with nitrogen, and the catalyst was removed by filtration and washed with tetrahydrofuran. The solvent was removed under reduced pressure to provide the titled compound as a pale yellow solid (112 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Cl)=[C:11]([CH3:22])[CH:10]=2)[N:4]=1.[H-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:21])=[C:11]([CH3:22])[CH:10]=2)[N:4]=1
Reactant: COc1nn(-c2ccc(NC(=O)CCCCl)c(C)c2)c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nn(-c2ccc(N3CCCC3=O)c(C)c2)c(=O)o1

Procedure:
The latter compound was prepared by reacting 5-methoxy-3-(4-(4-chlorobutanoylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with sodium hydride in dioxane at room temperature and purifying the crude product by column chromatography (silica gel, methylene chloride:methanol=98:2).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C(Cl)Cl>[C:30]1([CH2:36][C:37]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added phenylacetyl chloride (47.7 μL, 0.36 mmol). The resulting mixture was stirred at RT for 16 h. Then, H2O (3 mL) was added and the mixture was extracted with DCM (2×5 mL). The combined organic extracts were concentrated and the residue was dissolved in MeOH (1 mL). The solution mixture was purified by preparative HPLC (10-100% of MeCN (0.1% TFA)/H2O (0.1% TFA) to give the title compound as an off-white thick oil. MS (ESI, positive ion) m/z: 396 (M+H).
Reaction SMILES: I[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:5]2[CH:6]=[C:2]([B:28]3[O:29][C:30]([CH3:32])([CH3:31])[C:26]([CH3:33])([CH3:25])[O:27]3)[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:4]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Yield: 79.9 %

Procedure:
1 g (2.3 mmol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) was dissolved in 20 ml of dry toluene and 3.18 ml of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23 mmol), 20 mg (0.08 mmol) of palladium(II)chloride diacetonitrile complex, 80 mg (0.005 mmol) of S-Phos (2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl) and 774 μl (5.7 mmol) of triethylamine were added successively. The reaction mixture was submitted to microwave irradiation in a sealed vial at 90° C. for 30 minutes. The mixture was then filtered through a celite pad and the filtrate evaporated in vacuo. The residue was taken up with dichloromethane and washed with water and the organic layer dried over sodium sulphate and evaporated again. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 1%), affording 800 mg (80%) of the title compound, crystallized from diethylether.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>N1C=CC=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([NH:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1)(=[O:40])=[O:39]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4Cl)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 46.5 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 2-chlorobenzenesulfonyl chloride (27 mL, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was purified by chromatography on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (14 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J=6.25 Hz, 6 H) 1.54 (m, 2 H) 1.67 (m, 1 H) 4.44 (t, J=7.71 Hz, 2 H) 7.57 (m, 7 H) 8.11 (d, J=8.46 Hz, 1 H) 8.52 (dd, J=8.09, 1.84 Hz, 1 H) 8.86 (dd, J=4.78, 1.84 Hz, 1 H) 11.24 (s, 1 H) 13.99 (s, 1 H). MS (ESI−) m/z 600 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[O:18]([CH2:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(Cl)Cl>[CH3:11][NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][C:26](=[O:27])[CH2:25][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]=1[C:4]#[N:5]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CNc1cccc(N)c1C#N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CNc1cccc(NC(=O)COc2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (3.3 g) in methylene chloride (50 ml) is added pyridine (3.6 ml), and thereto is added dropwise phenoxyacetyl chloride (6.2 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol to give the title compound (1.4 g) having the following physical properties.