Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Cl.[N:13]1([CH:28]2[CH2:34][CH:33]3[N:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:30]([CH2:31][CH2:32]3)[CH2:29]2)[CH2:18][CH2:17][C:16]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][NH:20][CH2:19]2)[CH2:15][CH2:14]1>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:20]2[CH2:19][C:16]3([CH2:17][CH2:18][N:13]([CH:28]4[CH2:29][CH:30]5[N:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:33]([CH2:32][CH2:31]5)[CH2:34]4)[CH2:14][CH2:15]3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N1C2CCC1CC(N1CCC3(CC1)CN(c1cccc(OC)c1)Cc1ccccc13)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of 3-methoxyphenylboronic acid (30 mg, 0.2 mmol), Cu(OAc)2H2O (2 mg, 5 mol %), 3 Å molecular sieves (75 mg) in 1 mL of CH2Cl2 were stirred at room temperature for 5 min. Ethyl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride 5c (42 mg, 0.1 mmol) was added to the reaction and mixture was stirred at room temperature for 24 h. The reaction was diluted with methanol, filtered and subjected to reverse-phase HPLC purification (2-50% CH3CN—H2O gradient, with 0.05% TFA, 15 min) to give pure ethyl 3-(2-(3-methoxyphenyl)-2,3-dihydro -1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC-MS: m/z [M+H]+ 490.0, retention time 2.61 min (10-90% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: CN(C)C=[CH:4][CH:5]1[CH:7]([CH2:8][C:9](=[O:11])[CH3:10])[C:6]1([CH3:13])[CH3:12].[O:15]=[O+][O-]>C(Cl)Cl>[CH3:12][C:6]1([CH3:13])[CH:7]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]1[CH:4]=[O:15]
Reactant: O=[O+][O-]
Reactant: CC(=O)CC1C(C=CN(C)C)C1(C)C
Solvent: ClCCl
Product: CC(=O)CC1C(C=O)C1(C)C
Temperature: 25 °C
Yield: 84.4 %

Procedure:
To a solution 2.4 g of 1-(3-(2-(dimethylamino)ethenyl)-2,2-dimethylcyclopropyl)-2-propanone, the product of Embodiment I, in 50 ml of methylene chloride was added 0.6 g of ozone over 20 min at -80° C. The resulting mixture was purged with air and 1.5 g of triethylamine was added dropwise at -30° C. The resulting mixture, after stirring and warming to room temperature, had a negative test to starch iodide paper. The reaction mixture was poured into 25 ml 1 N hydrochloride acid solution. The resulting mixture separated into two phases and the methylene chloride phase was washed with water, dried with MgSO4, filtered and stripped to yield 1.6 g of the desired product as an oil.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8].[Br:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][N:23]=1)[C:15](N(OC)C)=[O:16].[NH4+].[Cl-]>C1COCC1.O>[Br:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[CH:21]=[CH:22][N:23]=1
Reactant: CON(C)C(=O)c1ccnc(Br)c1
Reactant: COC(CCBr)OC
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CCC(=O)c1ccnc(Br)c1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a suspension of Mg (3.67 g, 153.01 mmol) in THF (40 mL) is added cat. Iodine, followed by a solution of 3-bromo-1,1-dimethoxy-propane (21.47 g, 117.30 mmol) in THF (40 mL). The mixture is stirred at room temperature for 2 h. Then the fresh prepared Grignard reagent is cooled down in an ice bath, and added to a solution of 2-bromo-N-methoxy-N-methyl-isonicotinamide (12.50 g, 51.00 mmol) in THF (50 mL) at 0° C. The mixture is warmed up to room temperature and stirred at this temperature for 2 h. Then the reaction mixture is cooled in an ice bath, sat. NH4Cl and water are added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 10%) to give 1-(2-Bromo-pyridin-4-yl)-4,4-dimethyoxy-butane-1-one (12.1 g, 82%) as a pale yellow oil. M/Z=288.14
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][CH:31]([N:34]6[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]6)[CH2:32][CH2:33]5)=[CH:24][CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(C2CCN(c3ccc(Br)cc3)CC2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(C2CCN(c3ccc(Nc4nc5c(-c6ccc(S(C)(=O)=O)cc6)cccn5n4)cc3)CC2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (55.0 mg, 0.191 mmol) and 1-[1-(4-bromo-phenyl)-piperidin-4-yl]-4-methyl-piperazine (70.0 mg, 0.207 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (22.0 mg, 0.0402 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as yellow solid (0.014 g, 13%). MP=237-240° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.6 Hz, 1H), 8.23 (d, J=7.7 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.63 (d, J=7.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.01-6.95 (m, 3H), 6.66 (s, 1H), 3.70-3.62 (m, 2H), 3.10 (s, 3H), 2.73-2.32 (m, 11H), 2.30 (s, 3H), 1.98-1.90 (m, 2H), 1.77-165 (m, 2H). MS=546 (MH)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH3:19].Cl>ClCCl>[CH2:18]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[C:24]([CH:25]=1)[C:11]([C:10]1[CH:14]=[CH:15][C:7]([C:6]([F:17])([F:16])[F:5])=[CH:8][CH:9]=1)=[O:12])[CH3:19]
Reactant: CCc1ccc(OC)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(OC)c(C(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Aluminium chloride (0.6 g, 0.004 mole) was stirred in dichloromethane (2 ml) and treated with 4-trifluoromethylbenzoyl chloride (1 g, 0.0048 mole) (ice-bath cooling) and then with 4-ethylanisole (0.6 g, 0.0044 mole) in dichloromethane (1 ml). The mixture was stirred at room temperature overnight and then poured into ice and concentrated hydrochloric acid and extracted with chloroform. The chloroform solution was washed with 10% NaHCO3 solution (100 ml), dried (MgSO4), filtered and evaporated to leave 5-ethyl-2-methoxy-4'-trifluoromethylbenzophenone (1.2 g) as a yellow oil. The latter was heated in 55% aqueous hydrogen bromide (27.5 ml) at 110°-120° C. for 5 hours. The mixture was evaporated to dryness to leave the required product.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([C:14]#[N:15])[CH2:7]C2C=CC=CC=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:26][N:27]=[C:28]=[S:29]>O1CCCC1>[CH3:26][NH:27][C:28](=[S:29])[C:6]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=1)([C:14]#[N:15])[CH3:7]
Reactant: N#CC(Cc1ccccc1)c1ccc(Cl)cc1
Reactant: CN=C=S
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(=S)C(C)(C#N)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
To a 10 ml tetrahydrofuran solution containing 1.00 g (6 mmole) of 4-chlorophenylmethylbenzylcyanide was added a 3.2 ml tetrahydrofuran solution containing 2 M of lithium diisopropylamide at -60° C. After stirring for 30 minutes under the same conditions, a 5 ml tetrahydrofuran solution containing 0.44 g (6 mmol) of methyl isothiocyanate was added to the mixture and the mixture was allowed to stand at room temperature overnight. The solvent was removed from the reaction mixture under reduced pressure and water was added to the residue. The mixture was extracted with 50 ml of ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography and recrystallized from hexane to obtain 0.45 g (yield: 31.4 %) of N-methyl-2-(4-chlorophenyl)-2-cyano-thiopropionamide.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.F[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]#[N:13].O>CS(C)=O>[N:3]1([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]#[N:13])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CC(C)COc1ccc(C#N)cc1F
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)COc1ccc(C#N)cc1-n1ccnc1
Temperature: 110 °C

Procedure:
A reaction mixture solution prepared by suspending 41.1 mg of 3-fluoro-4-hydroxybenzonitrile, 33.4 mg of isobutyl bromide and 62.2 mg of potassium carbonate in 1 mL of dimethylformamide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile. (2) A reaction mixture prepared by adding 15.7 mg of sodium hydride and 24.5 mg of imidazole to the crude product of 3-fluoro-4-(2-methylpropoxy)benzonitrile obtained above and suspending the above in 1 mL of dimethylsulfoxide was heated at 110° C. for 5 hours under a nitrogen atmosphere. After the addition of water to the reaction mixture solution, extraction was performed using ethyl acetate. The organic layer was washed with saline, followed by drying and concentrating under reduced pressure to obtain a crude product of 3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[N:13]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[NH4+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:13])=[O:12]
Reactant: COc1ccccc1CC(=O)O
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methoxyphenylacetic acid (10.0 g, 60.1 mmol) was dissolved in acetonitrile (15 mL). Subsequently, pyridine (2.84 g, 36.1 mmol) and di-tert-butyl dicarbonate [Boc2O (19.6 g, 90.2 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (7.1 g, 90.2 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 18 without purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.[NH2:24][C:25]1([CH2:28][OH:29])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21]([NH:24][C:25]4([CH2:28][OH:29])[CH2:27][CH2:26]4)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1
Reactant: NC1(CO)CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(CO)CC5)c4n3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
To a stirred mixture of 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and (1-aminocyclopropyl)methanol (34 mg, 0.39 mmol) in DMF (3 mL), was added EDCI (100 mg, 0.52 mmol) followed by DMAP (63 mg, 0.52 mmol). The mixture was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered. The crude product was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 35% acetonitrile/65% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(1,6-dimethyl-1H-indazol-3-yl)-N-(1-(hydroxymethyl)cyclopropyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 36%) as a white solid. MS: (M+H)+=377; 1H NMR (300 MHz, DMSO): δ 13.84 (s, 1H), 9.12 (s, 1H), 8.74 (s, 1H), 8.43-8.40 (m, 2H), 7.56 (s, 1H), 7.21 (d, 1H, J=8.4 Hz), 4.89 (brs, 1H), 4.16 (s, 3H), 3.62 (s, 2H), 2.55 (s, 3H), 0.97-0.86 (m, 4H).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:2]1.Cl.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1>CC(O)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:5][C:6]([C:7]([F:10])([F:9])[F:8])=[N:22]2)=[CH:17][CH:16]=1
Reactant: O=C(CC(=O)C(F)(F)F)C1CC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(C2CC2)n(-c2ccc(Br)cc2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
1-Cyclopropyl-4,4,4-trifluorobutane-1,3-dione (1.330 g) was added to a mixture of (4-bromophenyl)hydrazine hydrochloride (1.65 g) and AcOH (10 mL). The mixture was stirred at 120° C. for 1 hr. AcOH was removed in vacuo and the residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give 1-(4-bromophenyl)-5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole (2.2059 g) as a yellow oil.
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][C:10]1[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=1.[NH2:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:30]=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:32]([Cl:35])=[N:33][CH:34]=2)[CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:35][C:32]1[N:33]=[CH:34][C:29]([C:27]2[CH:26]=[C:25]3[C:21]([CH:22]=[N:23][N:24]3[CH3:41])=[C:20]([NH:19][C:16]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:9])[N:15]=3)=[O:18])[CH:28]=2)=[CH:30][C:31]=1[NH:36][S:37]([CH3:40])(=[O:39])=[O:38]
Reactant: Cc1cccc(C(=O)O)n1
Reactant: Cn1ncc2c(N)cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc21
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc3c2cnn3C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propen-1-amine (0.042 ml) was added to 6-methyl-2-pyridinecarboxylic acid (44 mg) in DCM (1 ml). The reaction was stirred at RT for 20 mins. N-[5-(4-Amino-1-methyl-1H-indazol-6-yl)-2-chloro-3-pyridinyl]methanesulfonamide (75 mg) in DCM (2 ml) was added and the reaction stirred for 30 mins. Approximately 4 ml saturated sodium bicarbonate (aq) was added followed by DCM (3 ml). The reaction was stirred vigorously. The DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method E). The pure fraction was evaporated to dryness to give title compound (6 mg)
Reaction SMILES: [CH2:1](Br)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[I-].[Na+].O1CCCC1>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1COCCN1
Reactant: BrCC1CCCO1
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C1COC(CN2CCOCC2)C1
Yield: 92 %

Procedure:
A mixture of 165 g of tetrahydrofurfuryl bromide, 348 g of morpholine, 5 g of sodium iodide and 500 g of tetrahydrofuran was heated under reflux for 50 hours. After cooling, diethyl ether was added to the reaction solution, which was filtered, concentrated in vacuum and purified by vacuum distillation, whereby 158 g of 4-tetrahydrofurfuryl-morpholine, designated [B-44], was obtained (boiling point 64° C./15 Pa, yield: 92%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccccc1N1CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 6.62 (m, 1H), 6.48 (m, 3H), 5.01 (s, 2H), 3.73 (s, 3H), 3.61 (m, 4H), 3.43 (m, 2H), 2.31 (s, 3H) ppm; MS (ES) M+H expected=439.0, found 439.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([N+:11]([O-])=O)=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[C:5]([NH2:11])=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1
Reactant: [H][H]
Reactant: CC(C)c1cc(Cl)nc(C(C)C)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)c1cc(Cl)nc(C(C)C)c1N

Procedure:
30.0 g of 6-chloro-2,4-diisopropyl-3-nitropyridine are dissolved in 450 ml of tetrahydrofuran and, after the addition of 30.0 g of Raney nickel (suspended in ethanol), hydrogenated under a hydrogen pressure of 20 bar at from +30° C. to +35° C. The reaction mixture is filtered over diatomaceous earth and the filtrate is concentrated. The residue is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 3). 6-Chloro-2,4-diisopropyl-3-aminopyridine is obtained in the form of a clear crystalline powder, m.p. 53°-56° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(C(C)C)CC)(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:29]
Reactant: O=C(Cl)CCCCCl
Reactant: CCOC(=O)Cc1ccccc1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccccc1NC(=O)CCCCCl
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of ethyl 2-aminophenylacetate (5.60 g, 0.031 mole) and diisopropylethylamine (7.08 ml, 0.042 mole) in dry THF (75 ml) was treated with 5 chlorovaleryl chloride (4.00 ml, 0.031 mole) and left to stir for 1 h. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (200 ml) and washed with 1M HCl (100 ml), dried (Na2SO4) and concentrated in vacuo to afford a beige solid. This was washed with n-pentane/ether (1:1) and dried to afford the title compound as a light beige solid (8.1 g, 91%).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:19][C:20]1[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[CH2:26][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2C)CCCC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (870 mg, 3.58 mM), a-bromo-o-xylene (662 mg, 3.58 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.21 g (98%) of the 9-[(2-methylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a dark oil. 1H NMR (DMSO-d6) δ 7.5-7.2 (m, 4H), 7.15 (t, 1H, J=8 Hz), 7.0 (t, 1H, J=8 Hz), 6.15 (d, 1H, J=8 Hz), 5.55 (s, 2H), 3.85 (s, 3H), 2.6 (m, 2H), 2.4 (m, 2H), 2.4 (s, 3H), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3010, 2952, 1724, 1671, 1653, 1604, 1460, 1444, 1290, 1174, and 1122. MS (ES) m/e 348.5.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(COC(=O)c2ccccc2)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.95 g) in pyridine (25 ml) was dropwise added a solution of benzoyl chloride (2.0 g) in methylene chloride (5 ml) over 5 minutes at 5° to 6° C. with stirring. The resultant mixture was stirred for 15 minutes at the same temperature and then at room temperature for 2 hours, and followed by stirring at 50° C. for an hour and a half. After the reaction was over, the pyridine was distilled off and to the residue was added ethyl acetate and water. The ethyl acetate layer was separated, washed with dil. hydrochloric acid twice and then aqueous solution of sodium bicarbonate, and dried over magnesium sulfate. The solvent was removed and the residue was soon crystallized by treating with diethyl ether and collected by filtration. These crude crystals were washed with a mixture of diethyl ether and a small amount of ethyl acetate to give crystals, which was recrystallized from ethyl acetate (25 ml) to give powders of diethyl 2-methyl-4-(2-nitrophenyl)-6-benzoyloxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 156° to 157° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH2:14].O>CCO>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([NH:14][CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Solvent: CCO
Solvent: O
Product: CNc1cc(F)cc(F)c1[N+](=O)[O-]
Reaction time: 4 h
Yield: 83 %

Procedure:
1,3,5-Trifluoro-2-nitrobenzene (3.0 g, 16.90 mmol) was dissolved in EtOH (29.7 mL) and Methylamine 40% in Water (1.44 mL, 17.80 mmol) was added dropwise at 0° C. The color went from bright yellow to an orange precipitate within 20 min. After 4 h at RT. 0.66 mL of Methylamine was added (9 mmol). To complete the reaction, an additional 0.26 ml (3.6 mmol) of Methylamine was added after 2 h at RT. The completion was achieved within 20 min. Water (75 mL) was added to the reaction mixture and the solid was isolated by filtration, washed with water (2*10 mL) and dried over high vacuum to afford 2.64 g of 3,5-difluoro-N-methyl-2-nitrobenzenamine (Yield: 83%) as an orange solid.