Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][CH:6]=[CH:5][N:4]=1.[C-]#N.[Na+].[CH3:14][N:15](C=O)C>O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:14]#[N:15])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(C)C=O
Reactant: COc1ncccc1CCl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1ncccc1CC#N

Procedure:
4 g of (2-methoxy-3-pyridyl)methyl chloride, 2.5 g of sodium cyanide and 10 ml of DMF were stirred under heating for 10 minutes. Water was added thereto, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The drying agent was removed, and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1), to give 2.5 g of a colorless oil.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:28]#[N:29])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:30]=[C:31](Br)[CH:32]=[N:33][C:11]2=3)(=O)=O)C=CC=CC=1.[CH3:35]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:18]2[C:13]3[C:12]4[CH:30]=[C:31]([CH3:35])[CH:32]=[N:33][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:28]#[N:29])[CH2:21][CH2:22]1)[CH3:27]
Reactant: CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN1CCC(Oc2c(C#N)ncc3[nH]c4ncc(C)cc4c23)CC1
Temperature: 100 °C
Yield: 51.4 %

Procedure:
A mixture of 9-benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (215 mg, 0.40 mmol), trimethylboroxine (167 μL, 1.2 mmol), cesium carbonate (156 mg, 0.48 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (96 mg, 0.04 mmol) in dioxane (2.0 mL) was degassed with argon and heated under microwave irradiation at 100° C. for 90 minutes. The reaction mixture was allowed to cool to ambient temperature, diluted with saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic phase was washed with brine (2×10 mL) and concentrated in-vacuo. The resultant residue was diluted with THF (10 mL), 1N aqueous potassium hydroxide (1 mL) added and the reaction mixture was then heated at 50° C. for 1 hour. The solvent was evaporated in-vacuo and the resultant residue was purified by chromatography (silica, 2 g column, Si-SPE, 0-10% 2-propanol in dichloromethane). The appropriate fractions were combined and evaporated in-vacuo and the resultant residue triturated with pentane (2×2 mL) to afford the title compound as an off-white solid (69 mg, 52%). LCMS (Method A): RT=2.46 min, M+H+=336.2. 1H NMR (400 MHz, CD3OD): 8.71 (s, 1H), 8.52 (dd, J=2.1, 0.7 Hz, 1H), 8.47 (dd, J=2.1, 0.9 Hz, 1H), 4.91-4.88 (m, 1H), 3.02-2.99 (m, 2H), 2.57 (s, 3H), 2.50 (q, J=7.2 Hz, 2H), 2.26-2.19 (m, 4H), 2.12-2.11 (m, 2H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Mg].Cl[CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5].Br[CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[C:13]([OH:18])=[C:12]([CH2:19][CH3:20])[CH:11]=1>C(OCC)C>[CH2:19]([C:12]1[CH:11]=[C:10]([CH2:9][CH2:3][Si:4]([CH3:7])([CH3:6])[CH3:5])[CH:15]=[C:14]([CH2:16][CH3:17])[C:13]=1[OH:18])[CH3:20]
Reactant: CCc1cc(CBr)cc(CC)c1O
Reactant: C[Si](C)(C)CCl
Agent: [Mg]
Solvent: CCOCC
Product: CCc1cc(CC[Si](C)(C)C)cc(CC)c1O

Procedure:
Mix magnesium turnings (240 mg, 10 mmol) and anhydrous ethyl ether under an inert atmosphere. Add a solution of chloromethyltrimethylsilane (1.9 g, 10 mmol) in anhydrous ethyl ether. Stir until the magnesium metal dissolves. Add a solution of 4-bromomethyl-2,6-diethylphenol (2.43 g, 10 mmol) in anhydrous ethyl ether and reflux the mixture until the reaction is complete. Pour onto a mixture of ice/hydrochloric acid and separate the layers. Wash the ethereal layer with water, dry (MgSO4) and evaporate to give the title compound which is purified by silica gel chromatography.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]=2)[CH2:7][CH2:6]1)=O.C([O-])([O-])=O.[K+].[K+]>>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([CH:8]1[CH2:9][CH2:10][NH:5][CH2:6][CH2:7]1)=[N:12][CH2:13][CH2:14]2
Reactant: COc1ccc2c(c1)CCN=C2C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1)CCN=C2C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a stirred solution of 2,2,2-trifluoro-1-[4-(6-methoxy-3,4-dihydro-isoquinolin-1-yl)-piperidin-1-yl]-ethanone (0.160 g, 0.470 mmol) was added a solution of 10% K2CO3 (2 ml). The cloudy mixture was stirred at RT overnight. The reaction mixture was extracted with EtOAc (3×5 ml), the combined organic extracts were washed with brine (1×5 ml), dried over MgSO4, filtered, and concentrated in vacuo to give the desired compound as a yellow oil (0.101 g, 0.413 mmol, 88% yield).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[NH3:13]>>[N:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([NH2:13])=[O:2])=[CH:7][CH:8]=1
Reactant: N
Reactant: COC(=O)CCc1ccncc1
Product: NC(=O)CCc1ccncc1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
The crude ester was dissolved in 250 mL of 7.1M methanolic ammonia solution and was stirred at room temperature for 65 hours. After the solvent and excess ammonia were removed by distillation under reduced pressure, the residue was dissolved in 150 mL of 1N HCl and extracted with dichloromethane to remove residual triphenylphosphine oxide. The aqueous phase was basified with 40 mL of 4N NaOH and then was extracted with ethyl acetate (5×300 mL). The dried (Na2SO4) extracts were evaporated to furnish 6 g of the amide. The aqueous layer was concentrated to dryness and triturated with tetrahydrofuran (4×100 mL) and evaporation of the tetrahydrofuran extracts yielded an additional 5 g of amide. The combined crude products were dried, triturated with ether and the solids were filtered to yield 10.7 g of 4-pyridinepropanamide, mp 164°-166° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1>CN(C)C=O.O>[N+:32]([C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][CH2:24][CH2:23][NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)([O-:34])=[O:33]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NCCOc2cccc([N+](=O)[O-])c2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) and potassium carbonate (1.3 g, 9.6 mmol) in N,N-dimethylformamide (10 mL) was treated with a solution of 1-(2-bromoethoxy)-3-nitrobenzene (1.2 g, 5.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 2 h and at 80° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude residue. This material was purified by flash column chromatography to give the desired product (1.0 g, 56%) as a yellow gum. LCMS for C19H24N3O5 (M+H)+: m/z=374.2.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:39])=[C:19]([C:21]2([CH:36]([F:38])[F:37])[CH2:23][N:22]2[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH:20]=1>CN(C=O)C.C1COCC1>[C:6]([O:5][C:3](=[O:4])[C:2]([O:1][CH2:23][C:21]([C:19]1[CH:20]=[C:15]([Br:14])[CH:16]=[CH:17][C:18]=1[F:39])([NH:22][S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[CH:36]([F:38])[F:37])([CH3:11])[CH3:10])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1(c1cc(Br)ccc1F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)OCC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])(c1cc(Br)ccc1F)C(F)F
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of tert-butyl α-hydroxyisobutyrate (533 mg, 3.32 mmol) in 4.5 mL DMF and 0.75 mL THF was added portion wise (133 mg, 3.32 mmol) sodium hydride at room temperature. After the reaction mixture had been stirring for 15 minutes, a solution of 2-(5-bromo-2-fluoro-phenyl)-2-difluoromethyl-1-(2-nitro-benzenesulfonyl)-aziridine (1 g, 2.22 mmol) was added. The reaction mixture was stirred at rt for 150 minutes and quenched with aqueous NH4Cl solution. TBME was added, the layers were separated, washed with brine and TBME. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 6/1->5/1 to give 1.10 g of the title compound as a pale yellow resin.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23]C(=O)C)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[K+].O>CO>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH:15]([CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)[OH:16])=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1ccc(C(=O)C2CCN(CCc3ccccc3)CC2)cc1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1ccc(C(O)C2CCN(CCc3ccccc3)CC2)cc1
Reaction time: 6 h
Yield: 21.2 %

Procedure:
To N-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]acetamide (40.0 g, 114 mmol) in methanol (900 ml) was added potassium borohydride (16 g, 300 mmol), in small portions, over a 6 hour period. Water (200 ml) was added and the solution was stirred for 20 hours. The solution was concentrated and partitioned between water and dichloromethane. The layers were separated, the organic layer dried (MgSO4), filtered, and concentrated. The resulting material was chromatographed on silica gel, eluting with 10% methanol in chloroform. The appropriate fractions were combined, evaporated, and the resulting solid recrystallized from 2-propranol/water to afford α-(4-aminophenyl)-1-(2-phenylethyl)-4-piperidine methanol as a white solid (7.5 g, 21%): m.p. 129°-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16](Cl)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>[C].[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Yield: 99.8 %

Procedure:
To a 10 ml of ethanol solution containing 0.28 g of 3(S)-(3-chloro-4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester were added a 0.2 ml of a 5 N sodium hydroxide solution and 0.1 g of 10% palladium carbon. Catalytic reduction was conducted at room temperature and atmospheric pressure (ordinary pressure). The reaction solution was filtered using Celite and concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The extract was dried over magnesium sulfate and concentrated to dryness under reduced pressure to thereby obtain 0.25 g of yellow amorphous solid 3(S)-(4-methoxyphenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:23][NH:22][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15]CCCC)=[O:14])=[CH:11][CH:10]=2)[N:7]=1.[Li+].[OH-]>C1COCC1>[NH2:1][C:2]1[C:3]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:23][NH:22][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:20][CH:21]=2)[N:7]=1
Reactant: CCCCOC(=O)c1ccc(Nc2nc(N)c3c(-c4ccncc4)c[nH]c3n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc(C(=O)O)cc2)nc2[nH]cc(-c3ccncc3)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.7 %

Procedure:
To a solution of butyl 4-(4-amino-5-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzoate (137 mg, 0.340 mmol) in THF (3 mL), aq. 1N LiOH (2.0 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 20 h. It was concentrated in vacuo. The residue was acidified with HOAc (2 mL), then was purified by HPLC to give the titled compound (55 mg). MS 347.2 (M+H); UV 203.8, 306.7 nm.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:19][CH2:18]/[CH:17]=[C:16](/[C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)\[CH3:20])=[CH:35][CH:36]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccc(C(C)C)cc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)C)cc3)cc2)cc1)OCC
Yield: 84.3 %

Procedure:
The title compound (410 mg, 84%) was prepared as a colourless solid from (E)-3-(4′-isopropyl-biphenyl-4-yl)-but-2-en-1-ol (266 mg, 1.00 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (250 mg, 1.05 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>[Cu].ClC1C=CC=CC=1Cl>[C:5]1([CH3:6])[CH:15]=[CH:16][CH:2]=[CH:3][C:4]=1[NH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Agent: [Cu]
Solvent: Clc1ccccc1Cl
Product: Cc1ccccc1Nc1ccc(C(=O)c2ccc(Nc3ccccc3C)cc2)cc1
Temperature: 180 °C
Yield: 277.8 %

Procedure:
4.4 g of 4,4'-diaminobenzophenon, 30.9 g of P-iodotoluene, 19.5 g of potassium carbonate anhydride and 10 g of copper powder were added to 70 ml of o-dichlorobenzene, and the mixture thus obtained was refluxed with stirring for twenty-four hours at 180° C. After the reaction, the mixture was filtered and washed with ethyl acetate. Then, the mixture was separated by silica gel column chromatography using chloroform, thereby obtaining 11.3 g of 4,4'-ditolylaminobenzophenon.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(NC(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ccc(NC(=O)c2ccccc2N)cc1
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a suspension of N-(4-dimethylaminophenyl)-2-nitrobenzamide (3.0 g) in ethanol (30 ml) was added a catalytic amount of 10% palladium/carbon and catalytic reduction was carried out at a pressure of 1-2.5 arms at room temperature for 4 hrs. After the filtration of 10 catalyst, the solvent was distilled off and crystallization of the residue from chloroform/ethyl acetate afforded N-(4-dimethylaminophenyl)-2-aminobenzamide (2.2 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Cl:8][C:6]1[CH:5]=[C:4]([B:9]2[O:10][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:11]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(O)C(C)(C)O
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC1(C)OB(c2cc(Cl)cc(Cl)c2)OC1(C)C
Yield: 73 %

Procedure:
The title compound (73%, oil) was prepared from 3,5-dichlorophenylboronic acid and pinacol.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:10][C:9]1([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[F:11])(C)(C)C.Cl.O>CO.C(O)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2([F:11])[CH2:10][CH:8]2[NH2:7])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1CC1(F)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCO
Product: NC1CC1(F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-(4-chlorophenyl)-2-fluoro-cyclopropyl)-carbamic acid tert-butyl ester from example P5c) (1.00 g; 3.5 mmol) was dissolved in methanol (10 ml) and a saturated solution of HCl in ethanol (10 ml) added. The solution was stirred at room temperature for 2 h then evaporated leaving a white solid. Water (50 ml) then added and mixture extracted twice with ethyl acetate. The aqueous phase was made alkaline with 2M NaOH and extracted twice with ethyl acetate. The extracts were dried (MgSO4) and evaporated. 0.60 g of 2-(4-chlorophenyl)-2-fluoro-cyclopropylamine was obtained in the form of a yellow oil (92% of theory) as a 7:3 mixture of cis/trans isomers.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17]C)=[O:15])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]1[C:25]([O:27][CH2:28]C)=[O:26]>CO>[CH3:1][O:2][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH3:17])=[O:15])[C:10]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:9]1[C:25]([O:27][CH3:28])=[O:26]
Reactant: CCOC(=O)c1c(-c2ccccc2)c(C(=O)OCC)n(CCCCl)c1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCn1c(C)c(C(=O)OC)c(-c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Yield: 32.8 %

Procedure:
Sodium methoxide (190 mg, 3.50 mmol) was added to a solution of diethyl 1-(3-chloropropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (1.1 g, 2.91 mmol) in methanol (10 mL) and stirred at reflux for 28 h. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in water and the aqueous layer was extracted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford dimethyl 1-(3-methoxypropyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (330 mg, 33%) as a yellow oil. The aqueous layer was acidified with 2N hydrochloric acid to pH 2 and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated to afford 4-methoxycarbonyl-1-(3-methoxypropyl)-5-methyl-3-phenyl-pyrrole-2-carboxylic acid (170 mg, 18%) as a pink oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[F:1])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
Following procedure A, 3,4-difluoronitrobenzene (401 mg, 2.52 mmol, 1.00 eq) and 4-tert-butylphenol (477 mg, 3.18 mmol, 1.26 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (522 mg, 3.78 mmol, 1.50 eq) was added and the reaction mixture was stirred at room temperature for 19 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:50) to afford the title compound as colourless oil (722 mg, 2.52 mmol, 99% yield). Rf=0.54 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C16H17FNO3+ [M+H]+ 290.1187. found: 290.1194. 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J=10.3, 2.7 Hz, 1H, aromatic H), 7.96 (ddd, J=9.1, 2.7, 1.5 Hz, 1H, aromatic H), 7.49-7.38 (m, 2H, aromatic H), 7.09-6.99 (m, 2H, aromatic H), 6.96 (dd, J=9.1, 8.0 Hz, 1H, aromatic H), 1.35 (s, 9H, C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 153.35, 152.23, 151.93, 151.82, 150.84, 148.70, 142.40, 142.33, 127.29, 120.68, 120.64, 119.38, 117.73, 117.71, 113.28, 113.05, 34.65, 31.54.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:36][N:35]=1
Reactant: COc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(C(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methoxyphenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (493 mg, 1.1 mmol) produced in Synthesis Example 33 in DMF (4.5 mL) was added hydrazine monohydrate (purity of 80%, 175 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methoxybenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (418 mg, yield 86%).
Reaction SMILES: C(C1C=CC=CC=1)C.[F:9][C:10]1[C:17]([F:18])=[C:16](C#N)[C:15]([F:21])=[C:14]([F:22])[C:11]=1[C:12]#[N:13].[H][H]>[Pd]>[F:9][C:10]1[C:17]([F:18])=[CH:16][C:15]([F:21])=[C:14]([F:22])[C:11]=1[C:12]#[N:13]
Reactant: [H][H]
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Agent: [Pd]
Solvent: CCc1ccccc1
Product: N#Cc1c(F)c(F)cc(F)c1F
Temperature: 190 °C

Procedure:
200 g of ethylbenzene, 0.30 g of 5% palladium/activated carbon, and 6.0 g of 2,3,5,6-tetrafluoroterephthalonitrile were added to a 1000 cc stainless steel autoclave in a nitrogen atmosphere. The gas phase was sufficiently replaced with a mixed gas of 41 vol % hydrogen and 59 vol % nitrogen, then the mixed gas was used to keep the pressure at 0.23 MPa and the temperature was maintained at 190° C. After 2, 4, and 6 hours, the reaction solution was analyzed by gas chromatography, whereupon the conversions of 2,3,5,6-tetrafluoroterephthalonitrile were found to be 23, 62, and 99% and the yields of 2,3,5,6-tetrafluorobenzonitrile (based on 2,3,5,6-tetrafluoroterephthalonitrile) were 22, 56, and 87%, respectively.