Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH2:24])[CH2:20]2)=[N:17][CH:18]=1>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:26])([F:25])[F:11])=[CH:18][N:17]=2)[CH2:20]1)=[O:10]
Reactant: O=C=Nc1ccccc1Br
Reactant: N[C@@H]1CCN(c2ccc(C(F)(F)F)cn2)C1
Solvent: CCOCC
Product: O=C(Nc1ccccc1Br)N[C@@H]1CCN(c2ccc(C(F)(F)F)cn2)C1
Reaction time: 18 h

Procedure:
A solution of 2-bromophenyl isocyanate (Aldrich Chemical Company) (27.4 ml, 0.222 mol) in dry diethyl ether (65 ml) was added dropwise over 0.5 h to an efficiently stirred solution of D2 (51.4 g, 0.222 mol) in dry diethyl ether (0.8 L) under argon at ambient temperature. After stirring for 18 h, a white precipitate was filtered off and washed with dry diethyl ether (2×150 ml). The solid was crushed to a fine powder and then re-stirred with diethyl ether (470 ml) for 4 h at ambient temperature. The insoluble product was filtered off, washed with diethyl ether (100 ml) and dried at 50° C./vacuum/24 h to afford title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:9]([OH:28])[CH2:10][N:11]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])(C)(C)C.N(CCO)(CCO)CCO>CO.[C].[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]([CH2:10][C@@H:9]([OH:28])[C@@H:8]([NH2:7])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: OCCN(CCO)CCO
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
The compound of formula 3a (100 g), 10% palladium carbon (10 g) and triethanolamine (2 g) were suspended in methanol and then hydrogenated at 40-45° C. for 2 h. After completion of the reaction (TLC monitoring), filtered the reaction mass to remove palladium carbon. cp. HCl (62 mL) was added to the filtrate, heated to reflux and maintained for 2 h. The reaction mass was cooled to ambient temperature, pH of the reaction mass was adjusted to 6.0-7.0 with 20% sodium hydroxide solution. Methanol was distilled off under vacuum at below 50° C. The resultant residue was dissolved in a mixture of isopropyl alcohol (300 mL) and purified water (600 mL) and pH was further adjusted to 9.0-10.0 with 20% sodium hydroxide solution at ambient temperature. The reaction mass was maintained for 10 h, cooled to 0-5° C., filtered and washed with purified water. The wet cake was suspended in isopropyl alcohol (350 mL), heated to reflux, and maintained for 30 min. The reaction mass was cooled to 2-4° C., maintained for 1 h., filtered and washed with isopropyl alcohol. The wet product was air dried to obtain the compound of formula 4 in 71.3 g (yield-95%) with HPLC purity of 99.76%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@H](Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1

Procedure:
trans-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, trans-4-(amino)cyclohexanol, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].Cl.[C:18]([C:22]1[CH:26]=[C:25]([NH2:27])[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=1)([CH3:21])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:18]([C:22]1[CH:26]=[C:25]([NH:27][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)n1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a mixture of phenyl chloroformate (170 mg, 1.1 mmol) and potassium carbonate (210 mg, 1.5 mmol) in DCM (3 mL) at 0° C., was added dropwise a solution of 3-tert-butyl-1-isopropyl-1H-pyrazol-5-amine hydrochloride (220 mg, 1 mmol) in N,N-diisopropylethylamine (130 mg, 1 mmol) and the reaction mixture was stirred at 0° C. for 3 h. The mixture was filtrated, concentrated under reduced pressure, and the residue dissolved in dichloromethane. The organic phase was washed water, brine and concentrated under reduced pressure to give the crude product which was purified via recrystallization from diethyl ether to afford phenyl 3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate (300 mg, 100%) as a colorless solid. LC-MS (ESI) m/z 302 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:7][NH:6][CH2:5]1.N12CCCNC1CCCC=C2.[NH2:19][C:20]1[N:25]=[C:24]([N:26]2[C:35]3[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=3[CH3:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]2)[C:23]([F:43])=[CH:22][C:21]=1[F:44]>N1C=CC=CC=1>[NH2:3][CH:4]1[CH2:7][N:6]([C:33]2[C:34]([CH3:36])=[C:35]3[C:30]([C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27][N:26]3[C:24]3[C:23]([F:43])=[CH:22][C:21]([F:44])=[C:20]([NH2:19])[N:25]=3)=[CH:31][C:32]=2[F:38])[CH2:5]1
Reactant: NC1CNC1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c12
Agent: C1=CN2CCCNC2CCC1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(N2CC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c12
Temperature: 100 °C
Reaction time: 0.1 h
Yield: 10.3 %

Procedure:
A solution of 70 mg of 3-aminoazetidine dihydro-chloride, 200 mg of 1,8-diazabicyclo[5,4,0]undecene, and 300 mg of pyridine was stirred at 100° C., and 110 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was added to the solution and the solution was stirred at 100° C. for 6 minutes. The solvent was distilled off the reaction solution, and to the residue was added one drop of acetic acid and 3 ml of ethanol with heating, and the solution was allowed to stand. The solid precipitate was collected and dried to obtain 13 mg of the title compound as a pale yellow powder.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)=[N:13][CH:14]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N)cn2)cc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(Oc2ccc(Nc3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.2 mL, 8.4 mmol) was added to a suspension of ethyl 3-(4-(5-aminopyridin-2-yloxy)phenyl)propionate (1.2 g, 4.2 mmol), 3,4-dichlorophenylboronic acid (1.6 g, 8.4 mmol), anhydrous copper acetate (0.762 g, 4.2 mmol) and molecular sieves 4A (5 g) in dichloromethane (24 mL), and the resulting reaction solution was stirred overnight at room temperature. After the resulting solution was filtered through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.5 g of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[C:11]([NH2:12])=[C:10]([F:13])[C:9]([CH3:14])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:11]([NH:12][C:1](=[O:3])[CH3:2])=[C:10]([F:13])[C:9]([CH3:14])=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c(N)c1F
Solvent: Cc1ccccc1
Product: CC(=O)Nc1c(Cl)ccc(C)c1F

Procedure:
Acetylchloride (2.56 mL, 36.0 mmol) was added to a mixture of 6-chloro-2-fluoro-3-methyl-aniline (5.00 g, 31.3 mmol) and toluene (200 mL), additional toluene (50 mL) was added and the mixture was heated to reflux for 3 h. The reaction mixture was cooled with an ice bath and the formed precipitate was filtered off, washed with cold toluene and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[CH:7][C:6]=1[O:16][CH3:17])[CH3:2].Cl.[Cl:20][C:21]1[C:22]([F:29])=[C:23]([NH:27]N)[CH:24]=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:24]3[C:23](=[C:22]([F:29])[C:21]([Cl:20])=[CH:26][CH:25]=3)[NH:27][C:13]=2[CH3:14])[CH:8]=[CH:7][C:6]=1[O:16][CH3:17])[CH3:2]
Reactant: CCOC(=O)c1cc(SCC(C)=O)ccc1OC
Reactant: NNc1cccc(Cl)c1F
Agent: Cl
Product: CCOC(=O)c1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1OC

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-Methoxy-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CCO>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1
Reactant: Clc1cnccn1
Reactant: NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: NCC1CCN(c2cnccn2)CC1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A mixture of chloropyrazine (14.3 g), 1-(piperid-4-yl)methylamine (14.25 g), sodium carbonate (11.4 g) and 3-methyl-1-butanol (100 ml) was stirred and heated under reflux for 64 hours, cooled to ambient temperature and filtered. The solvent was removed in vacuo and the residual oil was distilled to give 1-[1-(pyrazin-2-yl)piperid-4-yl]methylamine as a pale yellow oil (16.2 g), b.p. 136°-160° C. at 0.6 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([F:26])[CH:15]=3)[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][CH3:30])=[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=12)[CH3:2].O1CCCC1.[BH4-].[Na+]>CO>[CH2:29]([O:28][C:7]1[C:8]2[C:9](=[O:27])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([F:26])[CH:15]=3)[CH:11]([OH:13])[C:12]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=12)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)cc1F
Reaction time: 0.08 h
Yield: 107.8 %

Procedure:
Ethyl {4-[4,9-bis(ethyloxy)-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate (24 g, 51.6 mmol) was suspended in methanol (75 ml) and tetrahydrofuran (200 ml) and cooled to 5° C. in an ice bath. Some solid did not go into solution. Sodium borohydride (2 g, 51.6 mmol) was added portionwise over 2 minutes (effervescence). Undissolved solid slowly went into solution and the colour lightened from dark brown to light brown. LC/MS after 5 minutes and 30 minutes indicated that the reaction had not proceeded to completion. Therefore, after 30 minutes, more sodium borohydride (1 g, 26.3 mmol) was added in one portion (effervescence). LC/MS after a further 30 minutes showed no starting material remaining. The mixture was concentrated in vacuo to give a brown oil that was partitioned between ethyl acetate (300 ml) and water (500 ml). The aqueous layer was further extracted with ethyl acetate (2×100 ml). Combined organics were washed with brine, dried over magnesium sulphate and concentrated to give the title compound as a brown solid (26 g).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[N:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: O=C(O)c1cccnc1O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)cnc1O
Temperature: 75 °C
Yield: 77.9 %

Procedure:
To a suspension of 5.0 g (35.9 mmol) of 2-hydroxy-nicotinic acid in 30 ml acetic acid was added dropwise 7.5 g (46.7 mmol) bromine. The mixture was maintained at 70-80° C. overnight. The mixture was cooled and the acetic acid was removed under reduced pressure. Water (100 ml) was added and the product was filtered and washed with water (3×100 ml). The solid was dried in a vacuum oven at 65° C. for 48 hours to provide 6.1 g (78% yield) of the title compound. MS: m/z (APCI, AP+) 219.0 [M.]+. CHN Analysis: Calcd: C, 33.06; H, 1.85; N, 6.42. Found: C, 32.91; H, 1.78; N, 6.23.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([CH3:9])=[N:3]1.C([O:12][CH:13]=[C:14]([C:18]#[N:19])[C:15]([O-])=O)C>C(O)C>[C:18]([C:14]1[C:13](=[O:12])[N:3]2[CH:4]([CH3:9])[CH2:5][CH2:6][CH2:7][CH2:8][C:2]2=[N:1][CH:15]=1)#[N:19]
Reactant: CCOC=C(C#N)C(=O)[O-]
Reactant: CC1=NC(N)CCCC1
Solvent: CCO
Product: CC1CCCCc2ncc(C#N)c(=O)n21
Temperature: -5 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
2.52 g. of 2-amino-7-methyl-3,4,5,6-tetrahydro-2H-azepine are dissolved in 25 ml. of ethanol and the solution is added dropwise to a solution of 3.38 g. of ethoxy-methylene-cyanoacetate in 25 ml. ethanol at -5° C. The reaction mixture is stirred for 1 hour at -5° C. and allowed to warm up to room temperature and boiled for 1 hour. The solvent is evaporated. The residual oil is dissolved in 40 ml. of benzene and the solution is shaken out once with 10 ml. of 5% by W/V sodium carbonate solution and twice with 10 ml. of water. The benzene layer is dried above sodium sulphate and evaporated after filtration. The residual oil is crystallized from acetone. 1.26 g. (31%) 3-cyano-6-methyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine is obtained melting at 154° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[C:16]([NH2:17])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>C1COCC1>[NH2:17][C:16]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH:36][C:27]4[CH:28]=[C:29]([C:32]([F:33])([F:35])[F:34])[CH:30]=[CH:31][C:26]=4[F:25])=[O:38])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[NH:14][N:15]=1
Reactant: Nc1ccc(-c2ccc3c(N)n[nH]c3n2)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1n[nH]c2nc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.44 mmol) of 6-(4-aminophenyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamine are partially solubilized in 2.5 ml of anhydrous THF. The mixture is then degassed for 15 minutes with argon. 61.55 μl (44.93 mg, 0.44 mmol, 1 eq.) of triethylamine are subsequently added. The solution is once again degassed for 15 minutes. Finally, 64.22 μl (91 mg, 0.44 mmol, 1 eq.) of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate are added dropwise. The mixture is stirred for 2 hours at ambient temperature under an inert atmosphere. After reaction, the mixture is filtered. The filtrate is concentrated. A beige solid is isolated. This crude product is subsequently purified on a C18 reverse-phase silica (13 g) column with an eluent gradient of 5% to 95% of acetonitrile in water. The fractions containing the expected product are lyophilized. A white solid is isolated (10 mg).
Reaction SMILES: [CH3:1][Li].CI.[Li].Cl.[CH3:7][O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][CH:14]2[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[CH2:17][CH2:16][N:15]2[CH3:23])=[CH:11][CH:10]=1>O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[C:19]([CH3:21])([CH3:20])[C:18]([CH3:1])([OH:22])[CH2:17][CH2:16][N:15]2[CH3:23])=[CH:24][CH:25]=1
Reactant: [Li]C
Reactant: COc1ccc(CC2N(C)CCC(=O)C2(C)C)cc1
Agent: Cl
Agent: [Li]
Solvent: CI
Solvent: O
Product: COc1ccc(CC2N(C)CCC(C)(O)C2(C)C)cc1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a mechanically stirred and nitrogen flushed ethereal solution (200 ml) of methyl lithium (prepared in the usual manner from 43 g of methyl iodide and 4.8 g of lithium) there is added in small quantities 9 g of 2-(p-methoxybenzyl)-1,3,3-trimethyl-4-piperidone hydrochloride. During the addition, which takes some 1.5 hour, the mixture is cooled with water. It is stirred at room temperature for 16 hours and finally refluxed for 1 hour. Then the lithium compounds are hydrolysed by careful addition of water (cooling with ice) and the basic material is extracted from the mixture with the aid of 4 N hydrochloric acid. Basification of the aqueous solution followed by extraction with ether and processing of the ethereal solution as usual, gives crystals which after recrystallization from petroleum ether melt at 55°-65° C. Yield 84%. Evidently a mixture of epimeric piperidinols has been formed.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.C1(P([Pd-4](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)C=CC=CC=1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(I)cc([N+](=O)[O-])c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Yield: 80.7 %

Procedure:
1-Iodo-3-methoxy-5-nitro-benzene (279 mg, 1 mmol), phenylboronic acid (146 mg, 1.2 mmol), potassium carbonate (2M, 1.0 ml) and tetrakis(triphenylphosphino)palladium(0) are dissolved in ethanol (0.5 ml) and toluene (10 ml) and the mixture heated to 90° C. for 24 h. The volatile components are removed in vacuo and the residue codistilled twice with toluene. Flash chromatography (silica, eluent dichloromethane/cyclohexane 1:2) affords the product (185 mg, 81%) as light brown solid. MS: m/e=229 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.I.CS[C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[NH:24]>C(O)C>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:23]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)=[NH:24])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1
Reactant: CN(C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN(C)C1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 93.5 %

Procedure:
A solution of compound 113 (0.18 g, 0.704 mmol) in dry ethanol (10 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.4 g, 1.409 mmol) at room temperature and stirred for 24 h. Solvent was evaporated and crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 114 (0.24 g, 90%) as a solid. mp 113-115° C.; 1H NMR (DMSO-d6) δ 1.42-1.53 (m, 1H), 1.97-2.02 (m, 1H), 2.08-2.22 (m, 8H), 2.31-2.60 (m, 3H), 6.03 (s, 1H), 6.21 (brs, 2H), 6.65 (dd, 1H, J=1.2, 8.4 Hz), 7.09 (t, 1H, J=4.2 Hz), 7.20 (s, 1H), 7.28-7.31 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.88 (s, 1H), ESI-MS m/z (%): 365 (MH+, 39), 320 (38), 183 (76), 160 (100); ESI-HRMS calculated for C21H25N4S (MH+), Calculated: 365.1813: Observed: 365.1794.
Reaction SMILES: N[C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][C:5]=2[S:4][C:3]=1[CH2:17][CH3:18].FC(F)(F)C([O-])=[O:22].[K+].FC(F)(F)C(O)=O>>[CH2:17]([C:3]1[S:4][C:5]2[N:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][C:9](=[O:11])[C:10]=2[C:2]=1[OH:22])[CH3:18]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCOC(=O)c1nc2sc(CC)c(N)c2c(=O)[nH]1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2sc(CC)c(O)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The diazonium fluoborate salt is prepared as in Procedure 63 from the amino compound produced in Procedure 51 yielding 0.03 mole of the required diazonium fluoborate. The latter is added in one portion to a solution of 0.03 mole of potassium trifluoroacetate in 13 ml. of trifluoroacetic acid at 0° C. The mixture is stirred at 25° C. for one hour and then refluxed overnight. The trifluoroacetic acid is evaporated in vacuo to give a residue which is triturated with water and filtered to give the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].C1N=C[N:28](C(N2C=NC=C2)=O)C=1.N>O1CCCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([NH2:28])=[O:20])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:23])([F:24])[F:25])([O-:3])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a heated solution (60° C.) of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (300 mg, 0.83 mmol) in tetrahydrofuran (25 ml) was added CDI (300 mg, 1.85 mmol, 2.2 eq) at reflux and then stirred for 1 hour at 60° C. (oil bath temperature). The resulting solution was poured into ammonia (25 ml) at room temperature and stirred for an additional 1 hour. The contents were diluted with water (100 ml) and the resulting mixture was extracted with ethyl acetate (3×100 ml). The organic layers were combined, washed with saturated aqueous sodium chloride (100 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to afford 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetamide as yellow solid (220 mg, 74%). (ES, m/z) [M+H]+ 362; 1H NMR (300 MHz, DMSO): δ 8.06 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.27 (d, J=4.2 Hz, 1H), 7.07 (s, 2H), 6.85 (dd, J=2.4 Hz, 9.3 Hz, 1H), 3.82 (s, 2H), 3.40-3.55 (m, 2H), 1.90-2.10 (m, 4H), 1.10-1.50 (m, 4H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:26][C:10]3=[CH:11][C:12]4[C:13]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:24]([C:13]1([CH2:22][CH3:23])[C:12]2[CH:11]=[C:10]3[NH:26][C:7]([C:3]4[C:2]([NH:1][C:33]([N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:34])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[N:15]([CH:18]([CH3:20])[CH3:19])[C:14]1=[O:21])[CH3:25]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Reactant: O=C(Cl)N1CCCCC1
Product: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4NC(=O)N4CCCCC4)[nH]c3cc21
Yield: 15 %

Procedure:
Piperidine-1-carboxylic acid[3-(7,7-diethyl-5-isopropyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-7,7-diethyl-5-isopropyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.43 mmol) and piperidine-1-carbonyl chloride (63 mg, 0.43 mmol). 30 mg (15%) of the title compound were obtained.