Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(F)cc1Br
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(C=O)c(F)cc1Br
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-bromo-4-fluoro-1-methoxybenzene (4.10 g) and titanium tetrachloride (4.4 mL), dichloromethyl methyl ether (3.5 mL) was added under ice cooling, and then the reaction mixture was stirred at 0° C. for 2.5 hours. To the reaction mixture was added chloroform, and the reaction mixture was poured into ice water, and then stirred at room temperature for 1 hour. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was added hexane and the produced solid was filtered to give the titled compound (1.61 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:21])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccc(Cl)nc3)nc(NN)nc21
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)nc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (6-chloro-pyridin-3-yl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and 2,4-pentanedione.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]1([F:35])[CH2:31][CH:30]1[C:32](O)=[O:33]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:30]5[CH2:31][C:29]5([F:35])[F:28])=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CC1(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CC1(F)F

Procedure:
The title compound, white solid (92 mg, 85%), MS (ISP) m/z=435.4 [(M+H)+], mp 184.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2,2-difluorocyclopropane-carboxylic acid.
Reaction SMILES: [O:1](S(C(F)(F)F)(=O)=O)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].O[C:17]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][C:18]=1[O:31][CH3:32].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:32][O:31][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:17]=1[O:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(OC)c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
17.7 ml of Tf2O was added to a solution of 16.8 g of ethyl 4-hydroxy-3-(methyloxy)-5-nitrobenzoate and 11.3 ml of pyridine in 500 ml of CHCl3 at 0° C. The mixture was stirred for 30 min, then washed successively with water, HClaq, and saturated NaHCO3aq, dried over Na2SO4, and concentrated. The residual solid was washed with a mixed solvent of CHCl3 and n-hexane to give a 22.0 g of the intended compound as a pale orange solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5])[CH3:2].Cl[CH:16]([P:20]([O:25][CH2:26][CH3:27])(=[O:24])[O:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:19][CH2:18][CH2:17][CH2:16][P:20](=[O:24])([O:25][CH2:26][CH3:27])[O:21][CH2:22][CH3:23])[CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5])[CH3:2]
Reactant: CCCC(Cl)P(=O)(OCC)OCC
Reactant: CCn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)n(CC)c(=O)n2C)OCC

Procedure:
9.7 g (0.05 mol) of 1-ethyl-3-methylxanthine were stirred at 70° C. for 6 hours with 12.7 g (0.06 mol) of diethyl chlorobutanephosphonate and 8.3 g of potassium carbonate. The solution was filtered, the solvent was evaporated, and the residue which remained was chromatographed (eluent: ethyl acetate/methanol 10: 1) and crystallized from ethyl acetate/diisopropyl ether.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([N:18]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)[CH2:17][C:16]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:31][CH:30]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(C(=O)OC)cc3)cc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(=O)OC)cc3)C(=O)c3ccc(C(C)(C)C)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure E using methyl 4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]benzoate and 4-tert-butylbenzoyl chloride as a colorless oil (63%). 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.3 Hz, 2H), 7.48-7.29 (m, 7H), 7.28-7.07 (m, 5H), 4.80-4.62 (m, 2H), 4.55-4.40 (m, 2H), 3.92 (s, 3H), 2.61 (t, J=7.7 Hz, 2H), 1.66-1.53 (m, 2H), 1.40-1.23 (m, 11H), 0.92 (t, J=7.4 Hz, 3H). M+ (ESI): 572.5. HPLC, Rt: 6.22 min (Purity: 99.5%).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][NH:10][NH2:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:21](OC)(=[O:26])[CH2:22][C:23]([CH3:25])=O>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][N:10]2[C:21]([OH:26])=[CH:22][C:23]([CH3:25])=[N:11]2)=[CH:7][CH:6]=1
Reactant: COC(=O)CC(C)=O
Reactant: COc1ccc(CNN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(C)cc2O)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution containing 2.75 g of (4-methoxybenzyl)hydrazine dihydrochloride in 50 ml of toluene was treated with 1.7 ml of triethylamine at rt and then stirred for 5 min. The mixture was then treated with 1.32 ml of methyl acetoacetate and heated at 100° C. for 15 min. The solvent was evaporated under reduced pressure and then the residue partitioned between dichloromethane/10% citric acid and extracted three times. Combined extracts were washed with brine, then dried over anhydrous magnesium sulphate, filtered and evaporated to give a yellow solid. The solid was purified by flash chromatography on silica gel using methanol/dichloromethane (1:49) for the elution to give 2.3 g of 2-(4-methoxybenzyl)-5-methyl-2H-pyrazol-3-ol as a white solid. Mass spectrum (ES) m/z 219 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O.[CH3:48][O:49][C:50](=[O:71])[C@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[NH:52][C:53](=[O:63])[C@H:54]([CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[NH2:55].C(N1CCOCC1)C>CN(C)C=O>[CH3:48][O:49][C:50](=[O:71])[C@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[NH:52][C:53](=[O:63])[C@H:54]([CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[NH:55][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (0° C.) solution of benzyloxycarbonylglycine (955mg, 4.5 mmole) and 1-hydroxybenzotriazole (1.2 g, 9 mmole) in dimethylformamide (15 ml) is added dicyclohexylcarbodiimide (1.03 g, 5 mmole). The mixture is stirred for 1 hour at 0° C. A cooled solution of phenylalanyl-phenylalanine methyl ester trifluoroacetate (2.0 g, 4.5 mmoles, described in U.S. Pat. No. 3,917,578, noted above) in dimethylformamide (20 ml) and N-ethyl morpholine (0.58 ml) is added and the mixture is stirred overnight at room temperature. The mixture is filtered and the filtrate is evaporated. The residue is dissolved in ethyl acetate (100 ml) and the solution is filtered. The filtrate is washed with 10% aqueous citric acid solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The solution is dried over magnesium sulfate (anhydrous) and evaporated. The residue is crystalized from ethyl acetate-petroleum ether (30°-60°) to give the title compound as crystals, mp 122°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])C=O.[CH3:13][O:14][CH:15](OC)[O:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:13][O:14][CH:15]([O:16][CH3:17])[C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([F:1])[CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc([N+](=O)[O-])c(F)c1

Procedure:
A mixture of 0.5 g (2.96 mmole) of 3-fluoro-4-nitrobenzaldehyde, 1 mL of trimethylorthoformate, 0.020 g of p-toluenesulfonic acid monohydrate and 2 mL of methanol was heated at reflux for 1 hour. The mixture was cooled, and 1 mL of saturated aqueous sodium bicarbonate solution was added. The mixture was concentrated under reduced pressure, and the residue was partitioned between 30 mL of ethyl acetate and 30 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.64 g of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene (IV.2a) as a pale yellow oil. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6]
Reactant: C1CCNC1
Reactant: O=C(Cl)c1cccc(F)c1
Product: O=C(c1cccc(F)c1)N1CCCC1

Procedure:
3-Fluorobenzoyl chloride was reacted with pyrrolidine using General Method E1 or E2 to produce N-(3-fluorobenzoyl)pyrrolidine.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.C([Li])CCC.[CH:27](N1CCCCC1)=[O:28]>C1COCC1>[CH:27]([C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1)=[O:28]
Reactant: O=CN1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1C=O
Temperature: -72 °C
Yield: 68.4 %

Procedure:
A solution of 1D (1.75 g, 5 mmol) in dry THF (50 mL) under argon was cooled to −72° C. and treated dropwise with n-butyllithium (2.5 M in hexanes, 4 mL, 10 mmol) at such a rate so that the temperature did not exceed −65° C. Upon completion of the addition, the reaction was stirred at −72° C. for an additional hour. N-formyl piperidine (1.1 mL, 10 mmol) was added, and then the reaction was allowed to warm up to 0° C. and maintained there for an hour. The solution was quenched by the addition of 1 M aqueous HCl to bring the pH to 6-8. The reaction was stirred at RT for 5 min, extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (110 g) column chromatography, eluting with a gradient of EtOAc (0-30%) in hexane to give the title compound as a yellow solid (1.02 g, 68%). LC/MS (method A): retention time=4.24 min, (M+H-tBu)+=243. 1H NMR (CDCl3, 400 MHz): δ 10.25 (s, 1H), 10.15 (s, 1H), 8.86 (d, J=9.0 Hz, 1H), 8.00-8.02 (m, 2H), 7.87(d, J=9.0 Hz, 1H), 7.38-7.47 (m, 3H) 1.56 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 197.93, 153.16, 151.18, 138.26, 138.14, 136.51, 129.45, 129.27, 127.50, 126.78, 125.80, 82.03, 28.64.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:18]([CH:21]=[C:22]1[NH:27][CH2:26][CH2:25][CH2:24][S:23]1)([O-:20])=[O:19]>ClCCl>[C:1]1([CH2:7][C:8]([N:27]2[CH2:26][CH2:25][CH2:24][S:23][C:22]2=[CH:21][N+:18]([O-:20])=[O:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CCCSC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenylacetyl chloride (4.8 g) in dry dichloromethane (30 ml) at -20° C. was added triethylamine (5.2 ml) over a period of 20 minutes, followed by 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (3.2 g) in dry dichloromethane (30 ml) over a period of 20 minutes. The reaction mixture was allowed to warm to ambient temperature with stirring over a period of 30 minutes and was then worked up in a similar manner to that described in Example 1 to yield the required product as a white crystalline solid m.p. 121°-122° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CC[N:45](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CO.C(Cl)Cl>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)(=[O:36])[NH2:45]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.03 h

Procedure:
In a 10 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200 mg, 324 μmol, Eq: 1.00) was combined with CH2Cl2 (5.43 ml) to give a suspension. DIPEA (50.3 mg, 68.0 μl, 389 μmol, Eq: 1.2) and HATU (136 mg, 357 μmol, Eq: 1.1) were added. The reaction was stirred for 2 minutes and 2M ammonia (811 μl, 1.62 mmol, Eq: 5) in methanol was added. The reaction mixture was stirred for 4 h.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:19][CH2:18]1)([O-])=O.O.NN>C(O)C.[Ni]>[O:26]1[CH2:27][CH2:28][CH:23]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:5]3[C:4]([NH2:1])=[CH:9][CH:8]=[C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])[CH:6]=3)[CH2:22][CH2:21]2)[CH2:24][CH2:25]1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(OCC(F)(F)F)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A stirred solution of N-{2-nitro-5-[(2,2,2-trifluoroethyl)oxy]phenyl}-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D56, 210 mg, 0.52 mmol) in ethanol (15 ml) at room temperature under argon was treated with Raney Nickel (20 mg) followed by dropwise addition of hydrazine hydrate (0.16 ml, 5.0 mmol). The mixture was maintained at room temperature for 1 hr, then filtered through Kieselguhr and the filtrate concentrated under vacuum to leave the title compound as a pale grey solid (190 mg, 98%).
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH3:13])[CH3:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1>[C:1]([NH:9][C@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH3:13])[CH3:12])(=[S:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](NC(=S)c1ccccc1)C(C)C
Yield: 45 %

Procedure:
Heat at reflux for 6 hours a solution of 0.025 mol (6.3 g) of ethyl N-benzoylvalinate obtained in Step B and 5.6 g of phosphorus pentasulphide in 120 ml of pyridine, and evaporate to dryness. Take up the residue in water and ethyl acetate. Wash the organic phase with a 2N hydrochloric acid solution, dry, filter and evaporate to dryness. The ethyl N-thiobenzoylvalinate obtained is purified by chromatography on a column of silica (eluant:ethyl acetate/hexane:25/75).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Mg].II.C[Mg]Br.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1.CCOCC>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1cc(C)ccc1Br
Agent: C[Mg]Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cc1OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
A solution of 2-bromo-5-methylanisole (3.8 g) [obtained as described in J. Gen. Chem. U.S.S.R., 1932, 2, 455 (Chemical Abstracts, 1933, 27, 962)] in THF (50 ml) was added to magnesium turnings (0.47 g) and a catalytic amount of iodine under an atmosphere of argon. A catalytic volume of 1M methyl magnesium bromide in ether was added and the mixture was heated 50° C. for 1 hour, and then cooled to 0° C. Tributyltin chloride (5.6 g) was added dropwise over 5 minutes and the mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue partitioned between ether (50 ml) and saturated ammonium chloride solution (50 ml). The organic phase was separated and washed with saturated ammonium chloride solution (2×20 ml). The ether layer was separated, diluted with ethyl acetate (50 ml), and washed with water (25 ml), followed by saturated sodium chloride solution (50 ml). Volatile material was removed by evaporation and the residue purified by distillation to give (2-methoxy-4-methylphenyl)tributyl tin (B) (4.8 g), as an oil, b.p. 190° C. at 0.05 torr; NMR: 0.75-1.7 (complex m,27H), 2.4(s,3H), 3.8(s,3H), 6.6(t,1H), 6.8(d,1H), 7.2(d,1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[CH:18][C:17]=2[C:31]#[N:32])=[CH:12][CH:11]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[N:19]=[CH:18][C:17]=2[C:31]#[N:32])=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2-c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccco1
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2-c2ccc(-c3ccco3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2-furanboronic acid instead of thiophen-3-boronic acid and 4-[5-[4-Bromophenyl]-4-cyano-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole instead of 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole in step 2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Br:23][C:24]1[C:29](F)=[CH:28][C:27]([NH2:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1>O>[Br:23][C:24]1[C:29]([O:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:28][C:27]([NH2:31])=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(N)c([N+](=O)[O-])cc2Br)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
5.2 g of 4-methanesulfonyl-phenol and 5.7 g of potassium carbonate were added in order to an N,N-dimethylformamide (50 ml) solution of 6.4 g of 4-bromo-5-fluoro-2-nitrophenylamine, and the reaction liquid was stirred at 120° C. for 3 hours. 200 ml of water was added to the reaction liquid, and the precipitated solid was taken out through filtration and dried to obtain the entitled compound as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1.S(=O)(=O)(O)O.[N:20]([O-])=O.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][N:20]=[CH:12][C:11]2=[O:13])=[O:14]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)c(C(C)=O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]ncc(=O)c2c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 16.7 %

Procedure:
To a solution of 3-acetyl-4-amino-benzoic acid methyl ester (2063 mg, 10.68 mmol) in acetic acid (39 mL) was added sulfuric acid (6.5 mL) on an ice bath, then, an aqueous solution (6.5 mL) of sodium nitrite (922 mg, 13.35 mmol) was added thereto, followed by stirring on the ice for 1 hour, and at room temperature for 2 days. The reaction mixture was concentrated until it reached half of the amount, water was added, then an aqueous solution of 2N sodium hydroxide was added on an ice bath to adjust the pH to 5. The insoluble matter was separated by filtration, then, the filtrate was extracted with ethyl acetate, the organic layer was dried over sodium sulfate and then evaporated. Diethyl ether was added to the resulting residue for solidification, the resulting solid was washed with diethyl ether, and 365 mg of the title compound (1.78 mmol, 16.6%) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:14]([NH2:17])=[CH:15][CH:16]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6].C(N(CC)CC)C.[Br:25][CH2:26][C:27](Br)=[O:28]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C:27](=[O:28])[CH2:26][Br:25])=[CH:15][CH:16]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: COC(=O)CCNC(=O)c1cc(I)ccc1N
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1cc(I)ccc1NC(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
21.0 g (60.5 mmol) of 3-iodo-6-amino-N-(2-methoxycarbonylethyl)benzamide prepared as in Example 1b) were dissolved in 270 ml of dichloromethane, and 12.5 ml (90.7 mmol) of triethylamine were added. At -30° C., 7.8 ml (90.7 mmol) of bromoacetyl bromide in 80 ml of dichloromethane were added dropwise. The mixture was stirred at room temperature for 2 h and then washed with 10% strength citric acid solution and sodium bicarbonate solution, dried and concentrated. The product was recrystallized from dichloromethane, resulting in 26.1 g (92%) of pale yellow crystals.