Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]1([CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Mg]Cl>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].C1COCC1>[C:10]1([CH3:18])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: COc1ccc(Cl)cc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Solvent: C1=CCCC=CCC1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2C)cc1
Reaction time: 0.17 h
Yield: 45 %

Procedure:
In the drybox, 54.0 mg (0.303 mm) of (Me3C)2PH(S) (from Experiment 18), 83.4 mg (0.303 mm) of Ni(COD)2 and 10.0 mL of THF were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperatureover a period of 10 min. After addition of 1.43 g (10.0 mm) of 4-chloroanisol, the resulting mixture was stirred for 5 min until the catalytic reaction was initiated by dropwise addition of 15 mL (15.0 mm, 1.0 M in THF) of o-tolylmagnesium chloride at room temperature over a period of 5 min. The resulting mixture was stirred at room temperature over 12 h before the reaction was quenched with 10.0 mL of H2O, and the mixture was diluted with 300 mL of Et2O. After separation of organic and aqueous phases, the organic phase was washed with 2×100 mL of H2O, and 100 mL of brine, then dried over mgSO4, filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography on silica gel (100:1-hexane:methyl t-butyl ether) to afford 0.90 g (45% yield) of 4-(o-tolyl)anisole.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:21][OH:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:30][S:31](O)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]([CH2:2][NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A round bottom flask was charged with (R)-2-(3-(aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 8; 0.20 g, 0.50 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.50 mmol), DIEA (0.13 g, 1.00 mmol), DMAP (0.067 g, 0.067 mmol), and THF (10 ml). The resulting solution was shaken vigorously at 60° C. for 8 hrs. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.075 g, 31%). 1H NMR (400 MHz, CD3OD) δ 7.50-7.41 (m, 2H), 7.15 (d, J=9.1 Hz, 1H), 7.04-7.00 (m, 2H), 6.09 (br s, 1H), 5.22-5.03 (m, 1H), 4.20-4.07 (m, 2H), 3.86-3.74 (m, 2H), 2.98 (s, 3H), 1.89-1.85 (m, 1H), 1.04-0.92 (m, 2H), 0.78-0.66 (m, 2H). MS: Calcd.: 478. Found: [M+H]+ 479.
Reaction SMILES: [N:1]1([CH:6]2[C:15](=[CH2:16])[C:14]3[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]=3[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].C(O)C>O>[N:1]1([CH:6]2[C:15](=[CH2:16])[C:14]3[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]=3[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=C1c2cc(C(=O)OCC)ccc2CCC1n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C1c2cc(C(=O)O)ccc2CCC1n1ccnc1
Yield: 84.5 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-7-(1H-imidazol-1-yl)-8-methylene-2-naphthalenecarboxylate (0.46 g), sodium hydroxide (0.8 g), ethanol (40 ml) and water (5 ml) is heated under reflux for 2 hours. The solution is evaporated, the residue is dissolved in water and the solution, acidified with acetic acid, is extracted with methylene chlorid. The organic layer is dried over sodium sulfate and evaporated to give 0.35 g of 5,6,7,8-tetrahydro-7-(1H-imidazol-1-yl)-8-methylene-2-naphthalenecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[C:16]2[CH:17]=[N:18][CH:19]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH3:10])=[CH:5][CH:4]=1.[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](Br)=[CH:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C>[C:31]([O:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:20]2[CH:19]=[N:18][CH:17]=[C:16]([C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH3:10])[CH:21]=2)=[CH:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(C)N2CCC[C@H]2c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccccc34)c2)cc1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A mixture of 3-{(S)-1-[(R)-1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine 4 (crude, 6.93 mmole), 3-bromo-indole-1-carboxylic acid tert-butyl ester (2.46 g, 8.32 mmole), Na2CO3 (35 mL, 35 mole, 1 M aqueous) in a mixed solution of 50 mL of toluene and 20 mL of ethanol was degased under vacuum. After heat at 80° C. for 1.5 hours, the reaction mixture was cooled to room temperature and dilutied with 150 mL of EtOAc, and washed by 2×100 mL of water. The organic layer was filtered and concentrated. The crude producte was purified by flash chromatography (Hexane 70%, EtOAc 30%) to give 3-(5-{(S)-1-[1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester 5 (2.02 g, 59% in two steps) as light brown gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:26]=[CH:25][C:17]3[C:18]([CH3:24])([CH3:23])[O:19][C:20](=[O:22])[NH:21][C:16]=3[CH:15]=2)=[CH:4][CH:3]=1.[OH:27]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:26]=[CH:25][C:17]3[C:18]([CH3:23])([CH3:24])[O:19][C:20](=[O:22])[NH:21][C:16]=3[CH:15]=2)=[O:27])=[CH:6][CH:7]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)NC(=O)OC3(C)C)cc1
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 7-[4-(4-methylphenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15]N(CC(NC3SC=CN=3)=O)[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1.CCN(C(C)C)C(C)C.[CH2:48]([CH:55]1CCNCC1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(C)C>[CH2:48]([CH:55]1[CH2:13][CH2:12][N:11]([C:6]2[C:5]([Br:26])=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCC(Cc3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 72 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 5-bromo-4-chloro-3-nitropyridin-2-amine (1.00 g, 3.96 mmol), DIPEA (3.5 eq, 13.86 mmol, 2.41 mL), isopropanol (20 mL) and 4-benzylpiperidine (1.1 eq, 4.36 mmol, 0.77 mL). Concentration in vacuo to half volume after 18 h gave a bright yellow solid, which was filtered and washed with cold water (2×5 mL) to give the product (1.12 g, 72%) as a yellow solid; δH (500 MHz, DMSO-d6) 1.38 (qd, br, J=12.2, 3.5 Hz, 2H, 2× piperidine CHAHB), 1.60 (d, br, J=10.9 Hz, 2H, 2× piperidine CHAHB), 1.69-1.76 (m, 1H, piperidine CH), 2.55 (d, J=7.1 Hz, 2H, 2× piperidine NCHAHA), 2.74 (t, br, J=11.9 Hz, 2H, 2× piperidine NCHAHA), 3.22 (d, br, J=12.5 Hz, 2H, PhCH2), 6.93 (s, br, 2H, NH2), 7.16-7.18 (1H, m, phenyl H-4), 7.19 (d, J=7.4 Hz, 2H, phenyl H-2 & H-6), 7.28 (t, J=7.1 Hz, 2H, phenyl H-3 & H-5), 8.13 (s, 1H, pyridine H-6);
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@H:10]2[CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>O1CCOCC1>[CH3:16][C@@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][N:9]1[C:6]1[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=1
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@H]2C)n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(NN)c(F)c(N2CCN(C)C[C@H]2C)n1
Temperature: 85 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
To a solution of 4-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (9.6 g, assumed 31.4 mmol) in 1,4-dioxane (126 mL) was added hydrazine monohydrate (8.5 mL, 175 mmol). The mixture was heated at 85° C. and stirred for 24 h. The mixture was cooled to room temperature and then concentrated in vacuo. The residue was partitioned between DCM (200 mL) and sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 4-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (8.04 g, >100% crude yield) as a dark orange oil. LCMS: (M+H)+: 254.9.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[C:10]([O:22][C:23]2[C:30]([CH3:31])=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[CH3:32])=[N:11][C:12]([NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[N:13][CH:14]=1.Br[CH:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:35]>CC#N>[Br:8][C:9]1[C:10]([O:22][C:23]2[C:30]([CH3:31])=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[CH3:32])=[N:11][C:12]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:35])[CH2:20][CH2:21]2)=[N:13][CH:14]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(NC2CCNCC2)ncc1Br
Reactant: CC(Br)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cc(C#N)cc(C)c1Oc1nc(NC2CCN(C(C)c3ccccc3)CC2)ncc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the TFA salt of 56 (1 mmol) in MeCN was added TEA (1.5 mmol) and (1-bromo-ethyl)-benzene (1 mmol) and the resulting mixture was stirred at RT for 6 h. After the reaction was complete, the solvent was removed and the residue was purified by preparative HPLC on a 30×100 mm C18 ODB column eluting with MeCN/H2O to afford 0.120 g (24.6%) of I-61.
Reaction SMILES: [O:1]=[C:2]([C:9]([F:12])([F:11])[F:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13]I.[Cl-].[NH4+].O>C(COC)OC.[Cl-].[Na+].O>[O:1]=[C:2]([C:9]([F:10])([F:11])[F:12])[CH:3]([CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CI
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (7.05 g of a 50% oil dispersion, 0.15 mol) was washed 3 times with 25 ml of dimethoxyethane to remove the oil and then suspended in 220 ml of dimethoxyethane, under an argon atmosphere and cooled in an ice bath. A solution of ethyl 3-keto-4,4,4-trifluorobutanoate (25.77 g, 0.14 mol) in 25 ml of dimethoxyethane was added dropwise from an addition funnel to the stirred suspension. After the addition was completed, the cooling bath was removed and the reaction mixture stirred for 30 minutes past the cessation of hydrogen gas evolution. Methyl iodide (43.0 ml, 0.70 mole) was added by syringe and the reaction mixture refluxed overnight. The reaction was cooled to room temperature and poured into a separatory funnel containing a 1:1:1 mixture of saturated ammonium chloride:brine:water. The layers were separated and the aqueous phase extracted with 100 ml ether. The combined organic phase and ether extract was washed with brine, dried over magnesium sulfate and filtered. The solvents were removed by distillation at atmospheric pressure using a Vigreaux column leaving ethyl 3-keto-2-methyl-4,4,4-trifluorobutanoate as the pot residue. Rf: (EtAc/hexane - 20:80)
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[Cl:10][CH2:11][C:12](O)=[O:13]>>[CH:8]1[C:9]([C:12]([CH2:11][Cl:10])=[O:13])=[C:1]([OH:2])[C:3]([OH:4])=[C:5]([OH:6])[CH:7]=1
Reactant: Oc1cccc(O)c1O
Reactant: O=C(O)CCl
Product: O=C(CCl)c1ccc(O)c(O)c1O

Procedure:
The condensation of pyrogallol and chloroacetic acid to form ω-chloro-2,3,4-trihydroxyacetophenone according to the invention is carried out using boron trifluoride as the condensing agent with a two-fold excess of chloroacetic acid. The reagents are mixed in any suitable manner and stirred together with moderate heating. When the reaction is complete the excess chloroacetic acid and boron trifluoride complex is removed by washing with water and filtering and, if desired, the product is recrystallized from water. Advantageously, the pyrogallol and chloroacetic acid are heated at a moderate temperature, say, about 65° C., until fusion is almost complete and the mixture is fluid. The boron trifluoride is then introduced under the surface at a moderate rate while the mixture is stirred and the temperature is maintained at about 65° C., and stirring and heating is continued until the reaction is complete, usually within about 3 hours. Higher or lower temperatures can be used, providing the temperature is high enough to give a fluid mix and not so high as to cause decomposition of the reagents or the product. Ordinarily, it will not be found necessary or advisable to heat above about 75° C. or to heat below about 60° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[CH:3]=1.C(O)=O>C(N(CC)CC)C.[Pd]>[OH:11][CH2:10][CH2:9][NH:8][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1c(NCCO)cc(Cl)cc1NCCO
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=[N+]([O-])c1c(NCCO)cccc1NCCO
Temperature: 70 °C

Procedure:
354 mg of palladium at a concentration of 10% on charcoal is added to 0.084 mole (23.1 g) of 4-chloro-2-(β-hydroxyethyl)amino-6-(β-hydroxyethyl)aminonitrobenzene in 23.7 g of triethylamine. 7 ml of formic acid are then run in dropwise. A high exothermicity is noted. The reaction mixture is heated to 70° C. for 1 hour 30. After dilution of the reaction mixture with ethanol, the catalyst is removed by hot filtration. The filtrate, evaporated to dryness under reduced pressure, enables a dry extract to be obtained. After dilution of the dry extract with water, the expected product precipitates. After being filtered off, washed with water and then dried under vacuum in the presence of phosphorus pentoxide, it is recrystallized twice from isopropanol. It melts at 103°-104° C., resolidifies and then melts at 112°-113° C.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:42])[NH2:26])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCc3nnn[nH]3)c3ccccc3)ccc21
Yield: 29 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 29% of theory, C26H26N10O (494.6); EKA mass spectrum: (M+H)+=495.
Reaction SMILES: C(O[CH:4]=[N:5][C:6]#[N:7])C.[NH2:8][CH:9]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[CH2:11][C:10]1([CH3:18])[CH3:17]>C(O)C>[C:6]([NH:5][CH:4]=[N:8][CH:9]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[CH2:11][C:10]1([CH3:18])[CH3:17])#[N:7]
Reactant: CCOC=NC#N
Reactant: CC1(C)Cc2sccc2C1N
Solvent: CCO
Product: CC1(C)Cc2sccc2C1N=CNC#N
Reaction time: 2 h
Yield: 55.9 %

Procedure:
2.7 g of N-cyanoimidoformic acid ethyl ester are added dropwise to a solution of 3.0 g of 4-amino-5,6-dihydro-5,5-dimethyl-4H-cyclopenta-[b]thiophene in 1.0 ml of ethanol. The exothermic reaction is complete after 2 hours. The reaction mixture is concentrated by evaporation. The crystalline residue is recrystallised from ether, yielding 2.2 g of N-cyano-N'-(5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-yl)-formamidine having a melting point of 118°-119° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[CH:15]1(C2C(I)=CC(C(O)=O)=C(C)C=2)C[CH2:16]1.IC1C(C)=CC(C)=C(C=1)C(O)=O>>[CH:14]1([C:4]2[C:3]([CH:1]=[O:2])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:13])[CH:5]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)c1cc(C=O)c(C)cc1C
Reactant: Cc1cc(C2CC2)c(I)cc1C(=O)O
Agent: Cc1cc(C)c(C(=O)O)cc1I
Product: COC(=O)c1cc(C=O)c(C2CC2)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 83.2, except 4-cyclopropyl-5-iodo-2-methylbenzoic acid (compound 86.3) was used in place of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:30][C:31]1[CH:32]=[C:33]([CH3:39])[C:34](=[O:38])[N:35]([CH3:37])[CH:36]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:30][C:31]2[CH:32]=[C:33]([CH3:39])[C:34](=[O:38])[N:35]([CH3:37])[CH:36]=2)[C:9]2[C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylate (Step 1.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.94 min (HPLC 1); tR: 1.13 min (LC-MS 2); ESI-MS: 535 [M+H]+ (LC-MS 2); Rf=0.45 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [N:1]1([NH:7][C:8](=O)OC(C)(C)C)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27](C=O)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[N:1]1([N:7]=[CH:8][C:27]2[CH:30]=[CH:31][C:24]([C:23]([F:33])([F:32])[F:22])=[CH:25][CH:26]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(C=NN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Tert-butyl piperazin-1-yl-carbamate (403 mg, 2.0 mmol) was suspended in methylene chloride (4 ml), to which trifluoroacetic acid (1.6 ml) was added, and the mixture was stirred at room temperature for 5 minutes. To which 4-(trifluoromethyl)benzaldehyde (0.3 ml, 2.2 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into sodium hydrogencarbonate aqueous solution, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=9/1) to afford piperazin-1-yl-(4-trifluoromethylbenzylidene)-amine (432 mg, yield 84%) as a colorless crystalline powder.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([CH2:13][C:14](=[O:33])[N:15]3[C:23]4[C:18](=[C:19](C5CCCN(CCC)C5)[CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[NH:10][C:9](=[O:34])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.CN(C)[CH2:38][CH2:39][CH2:40]N=C=NCC.N1(C2N=C(CC([O-])=O)NC(=O)C=2)CCOCC1.[Na+]>CN(C)C=O.N1C=CC=CC=1>[N:1]1([C:7]2[N:12]=[C:11]([CH2:13][C:14](=[O:33])[N:15]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH:17]4[CH2:38][CH2:39][CH2:40][CH:16]34)[NH:10][C:9](=[O:34])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCN1CCCC(c2cccc3c2CCN3C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2C2CCCC21
Temperature: 25 °C
Reaction time: 72 h
Yield: 143.4 %

Procedure:
320 mg of 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole [reference example 7d] and 424 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 525 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2d of example 1d) in 4 ml of N,N-dimethylformamide and 4 ml of pyridine. The reaction mixture is stirred at ambient temperature for 72 hours and then concentrated under reduced pressure. The residue is taken up in a mixture of water and ethyl acetate and the organic phase is washed successively with water, a 1M hydrochloric acid solution and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is triturated from methanol, filtered and washed with diisopropyl ether, so as to give 375 mg of 6-(morpholin-4-yl)-2-[2-oxo-2-(2,3,3a,8b-tetrahydrocyclopenta[b]indol-4(1H)-yl)ethyl]pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: C([O:4][C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]2[C:14]3=[N:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][C:18]([CH3:19])=[C:13]3[N:12]=[C:11]2[CH3:24])=[C:7]([Cl:27])[CH:6]=1)(=O)C.S(=O)(=O)(O)O.CO>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:27][C:7]1[CH:6]=[C:5]([OH:4])[CH:26]=[CH:25][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=[C:11]1[CH3:24]
Reactant: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(OC(C)=O)cc3Cl)c2n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Yield: 65.7 %

Procedure:
A mixture of methyl 3-(4-acetoxy-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (6.5 g), conc. sulfuric acid (3.0 ml) and methanol (60 ml) was refluxed under heating for 1.5 hr. The reaction mixture was diluted with chloroform (60 ml) and saturated aqueous sodium hydrogen carbonate solution was gradually added under ice-cooling. The organic layer was separated, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was washed with diethyl ether to give methyl 3-(2-chloro-4-hydroxybenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (3.81 g) as a pale-yellow powder.