Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: NCc1ccc(F)cc1
Product: Cc1cc(NCc2ccc(F)cc2)c2ccccc2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methylquinoline and 4-fluorobenzylamine.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])[O:11][CH2:12][CH3:13])[CH2:9][CH2:8]2)[CH:6]=1.[CH3:15][O:16]C1C=NN(CC#N)C=1>>[CH3:15][O:16][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10](=[NH:14])[O:11][CH2:12][CH3:13])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Reactant: COc1cnn(CC#N)c1
Product: CCOC(=N)C1(n2cc(OC)cn2)CC1

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 56, but using 2-(4-methoxy-1H-pyrazol-1-yl)acetonitrile as the starting material. 1H NMR (500 MHz, CDCl3) δ 1.37 (t, 3H), 1.63-1.72 (m, 4H), 3.76 (s, 3H), 4.16 (q, 2H), 7.17 (s, 1H), 7.35 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][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)C(C)C)(C)C>CN(C=O)C>[CH:9]1([NH:8][C:6]2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=[C:2]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]3)[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(N[C@H]2CC[C@H](O)CC2)nc1NC1CCCC1
Reaction time: 8 h

Procedure:
(2-Chloro-5-nitropyrimidin-4-yl)cyclopentylamine (6.18 mmol, 1.5 g.) and trans-4-aminocyclohexan-1-ol (7.42 mmol, 854 mg mL) were mixed in DMF (18 mL) and N,N-diisopropylethylamine (7.42 mmol, 1.29 mL) was added. The reaction mixture was stirred overnight. Solvent was removed in vacuo and the residue purified using column chromatography (SiO2, 1:1 n-hexanes/ethyl acetate→7:3 n-hexanes/ethyl acetate→ethyl acetate) to give the desired product (1.75 g, 88% yield). ES-MS: 322 (M+1). When the hydrochloride salt of an amine is used in place of the trans-4-aminocyclohexan-1-ol described above, 2 to 3 equivalents of N,N-diisopropylethylamine or sodium bicarbonate and tetrahydrofuran or acetonitrile were used as solvent.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][F:10].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])#[N:12].O>CN(C=O)C>[F:10][CH2:9][CH2:8][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]#[N:12]
Reactant: N#Cc1ccccc1O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1OCCF
Temperature: 70 °C
Yield: 84.7 %

Procedure:
K2CO3 (1.74 g, 12.5 mmol) and 1-bromo-2-fluoro ethane (0.78 mL, 10.47 mmol) were added to a solution of 2-cyanophenol 134 (0.5 g, 4.19 mmol) in anhydrous DMF (10 mL), and heated at 70° C. for 45 min. After completion, the reaction mixture was cooled to room temperature and water (10 mL) was added and the mixture extracted with diethyl ether. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on flash silica gel column chromatography (hexane:ethyl acetate=2:1) to give the compound 135 (0.586 g, 84%) as a white solid. 1H NMR (CDCl3, 300 MHz) d 7.51-7.58 (m, 2H), 6.98-7.07 (m, 2H), 4.89 (t, J=3.9 Hz, 1H), 4.73 (t, J=4.2 Hz, 1H), 4.40 (t, J=3.9 Hz, 1H), 4.31 (t, J=3.9 Hz, 1H). HRMS calculated for C8H7NOF (M+H)+: 152.0513. found 152.0539.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:12][CH:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1.N[C@H]1C2CCN(CC2)C1>>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16]1)[C@H:13]([NH:12][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[CH3:11])[CH2:14]2
Reactant: Cc1c(Cl)cccc1C(=O)O
Reactant: NC1CN2CCC1CC2
Agent: N[C@@H]1CN2CCC1CC2
Product: Cc1c(Cl)cccc1C(=O)N[C@@H]1CN2CCC1CC2

Procedure:
Proceeding as in Example 1, Method A, but replacing 2,3-dimethylbenzoic acid with 3-chloro-2-methylbenzoic acid and (RS)-3-amino-1-azabicyclo[2.2.2]octane with (S)-3-amino-1-azabicyclo[2.2.2]octane gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-2-methylbenzamide.
Reaction SMILES: [CH2:1]([C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]1(C)[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl.N1C=CC=C[CH:27]=1>>[C:16]1([CH3:27])[C:17]([S:20]([O:13][CH2:12][CH:9]2[CH2:10][CH2:11][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH2:8]2)(=[O:21])=[O:22])=[CH:18][CH:19]=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCC1=CCC(CO)CC1
Reactant: c1ccncc1
Agent: Cl
Product: CCCCCC1=CCC(COS(=O)(=O)c2ccccc2C)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-pentyl-3-cyclohexen-1-methanol (3.0 g) in pyridine (3.3 ml) at 0° C. was added p-toluenesulfonyl chloride (3.3 g). The reaction was stirred in an ice bath for 2 hours, and then stored at -20 ° C. for a further 16 hours. The reaction mixture was then poured into 2 M HCl (75 ml) and extracted with ethyl acetate. The combined organic layers were extracted with saturated sodium chloride and dried over sodium sulfate. The solvent was removed in vacuo to produce 4-pentyl-3-cyclohexen-1-methanol toluenesulfonate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]=1[F:19].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C=O)C.O>[F:19][C:10]1[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 60 °C

Procedure:
4-Hydroxypiperidine (658 mg, 6 5 mmol) and 1,2-difluoro-4-(methanesufonyl)benzene (1.98 g, 5.1 mmol) were combined in DMF (5 mL). Sodium carbonate (705 mg, 6.7 mmol) was added and the mixture was heated at 60 ° C. for 18 h. The mixture was cooled to room temperature and then poured into a mixture of water (10 mL) and a saturated sodium chloride solution (10 mL). The mixture was extracted three times with ethyl acetate (15 mL) and the extracts were combined, washed with brine, dried (MgSO4), and concentrated under vacuum to afford 1.46 g of crude 1a, which was used in the subsequent step without purification: LC-MS 274.1 (MH+).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH2:14][S:15][C@@H:16]2[CH:27]([NH2:28])[C:26](=[O:29])[N:17]2[C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].F[C:31]1[NH:32][CH:33]=[C:34]([CH2:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[N:35]=1>C(#N)C>[CH3:12][C:13]1[CH2:14][S:15][C@@H:16]2[CH:27]([NH:28][C:31]3[NH:32][CH:33]=[C:34]([CH2:36][CH2:37][NH:38][C:39](=[O:44])[C:40]([F:41])([F:42])[F:43])[N:35]=3)[C:26](=[O:29])[N:17]2[C:18]=1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(NCCc1c[nH]c(F)n1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3nc(CCNC(=O)C(F)(F)F)c[nH]3)[C@H]2SC1
Yield: 71.6 %

Procedure:
A mixture of t-butyl 3-methyl-7-aminoceph-3-em-4-carboxylate toluene-p-sulphonate (0.442 g.) and 2-fluoro-4-(2-trifluoroacetylaminoethyl)imidazole (0.45 g.) was stirred in acetonitrile (dried over molecular sieve, 10 ml.) at 70°-75° for 1.5 hours. The mixture was filtered and the filtrate purified on silica gel (500 g.) eluted with methylene chloride containing 1%, 2%, 3%, 4% and finally 5% v/v methanol. The relevant fractions were combined to give t-butyl 3-methyl-7-[4-(2-trifluoroacetylaminoethyl)imidazol-2-yl]aminoceph-3-em-4-carboxylate (0.34 g.) which was used without further purification.
Reaction SMILES: Cl.[OH-:2].[Na+].[CH3:4][N:5]([CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:6].[C:17]1(C)[C:18](C)=[CH:19][CH:20]=[CH:21][CH:22]=1>O>[C:17]1([NH:5][C:7]([C:8]2[CH2:16][CH2:6][N:5]([CH2:7][C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][CH:9]=3)[CH2:4][CH:9]=2)=[O:2])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccccc1C
Reactant: [OH-]
Reactant: CN(C)Cc1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(Nc1ccccc1)C1=CCN(Cc2c[nH]c3ncccc23)CC1

Procedure:
A solution of the preceding hydrochloride in water was basified with aqueous sodium hydroxide and the resulting suspension extracted with dichloromethane (3×25 ml). The extracts were dried (MgSO4), evaporated and the residual gum (2.16 g) was combined with 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (1.75 g, 10 mmol) in xylene (50 ml) and the mixture stirred at reflux for 3.5 h. After decanting the mixture whilst hot, the supernatant was allowed to cool and the solid deposited collected and recrystallised twice from ethanol to leave the title compound as buff plates (0.21 g), m.p. 217°-220°; (Found C, 72.09; H, 5.98; N, 16.59. C20H20N4O requires C, 72.27; H, 6.06; N, 16.86%); δH (DMSO-d6) 2.36 (2H, br s, tetrahydropyridinyl CH2), 2.59 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.11 (2H, br s, tetrahydropyridinyl CH2), 3.75 (2H, s, ArCH2N), 6.60 (1H, br s, CR=CH), 7.00-7.06 (2H, m, ArH & 5-H), 7.28 (2H, t, J 8.3 Hz, ArH), 7.39 (1H, d, J 2.3 Hz, 2-H), 7.64 (2H, dd, J 8.6, 1.0 Hz, ArH), 8.03 (1H, dd, J 7.8, 1.2 Hz, 4-H), 8.20 (1H, dd, J 4.6, 1.5 Hz, 6-H), 9.60 (1H, s, NH), and 11.47 (1H, br s, 1-H); M/z (CI+, NH3) 333 (M+1)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([CH2:12]Cl)[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][CH:5]=1.C[N:15]([CH3:18])C=O>O>[C:4]1([CH2:12][C:18]#[N:15])[CH:9]=[CH:8][C:7]([CH2:10][C:1]#[N:2])=[CH:6][CH:5]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(CCl)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(CC#N)cc1
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 130 grams (2.65 moles) sodium cyanide in 200 ml of water was placed in a four-necked flask, equipped with a thermowell, mechanical stirrer, electrically heated addition funnel and a condenser. A solution of 200 grams (1.15 mole) of p-xylylene chloride in 200 ml of dimethyl formamide was added dropwise with constant stirring and such a rate as to maintain the reaction temperature at 60°-65°C. The p-xylylene chloride solution was maintained at about 60°C. to prevent solid precipitation. The reaction was exothermic and addition took 2 hours. At the completion of the addition, the temperature was maintained by external heating for an additional hour. The mixture was then poured into 2 liters of water. The precipitated solid was filtered and washed with an additional liter of water. The product yield was 85% (ca. 152 g.) of para-phenylene diacetonitrile having a melting point of about 95°-97°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(O)=O.[Na+].[Br:16]Br>C(Cl)Cl>[Br:16][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1cccnc1OC
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)cnc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dimethoxy-pyridine (104 g) in DCM (1 L) and a saturated aqueous solution of NaHCO3 (1.6 ml) at 0° C. was added bromine (120 g). The reaction was stirred for 2 hours at 0° C. The reaction mixture was quenched with Na2SO3 (saturated in water, 500 ml) and stirred for 30 min. The aqueous layer was extracted with DCM, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel with heptane and increasing amounts of ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]1[CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O.O.Cl>CCO>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]1[CH2:18][NH2:19]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CN2C(=O)c3ccccc3C2=O)n1C
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(=O)c(OCc2ccccc2)c(CN)n1C
Temperature: 4 °C
Yield: 92.3 %

Procedure:
10 g of 59 (26 mmol, 1 equiv) was dissolved in 100 ml EtOH. 17 ml N2H4 (5.5% aqueous) was added and the solution was refluxed for 3 hours. 59 did not fully dissolve until refluxing had begun. The solution was allowed to cool, at which point it solidified. Water was added and the pH adjusted to 1 with conc. HCl. After overnight cooling at 4° C., the solution was filtered. The pH of the filtrate was adjusted to 14 with 10 N NaOH and extracted with 5×100 ml CH2Cl2. The extracts were combined and dried over Na2SO4. The solvent was removed in vacuo to give 6.2 g of a white solid in 92% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]([NH:22][CH:12]1[CH2:11][CH2:10][CH2:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COc1cccc2c1CCCC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c1CCCC(NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-methoxy-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one (6.0 g) and benzylamine (3.4 ml) in toluene (60 ml) in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the residue in methanol (60 ml) was added sodium borohydride (1.2 g) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into ice-cold water and stirred for 30 minutes before adding ethyl acetate and brine. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate-methanol) over silica gel to afford N-benzyl-(1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (7.27 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Cl[C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[C:18]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])=[CH:28][CH:27]=2)[N:17]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.O>[C:10]([O:9][C:8](=[O:14])[NH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH2:22])=[C:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])=[CH:28][CH:27]=3)[N:17]=2)[CH2:2]1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Yield: 66.7 %

Procedure:
A solution of (R)-tert-butyl piperidin-3-ylcarbamate (416 mg, 2.079 mmol), 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (500 mg, 1.386 mmol), and N,N-diisopropylethylamine (0.484 mL, 2.77 mmol) in N-methyl-2-pyrrolidinone (3 mL) was heated to 120° C. overnight. The reaction mixture was diluted with water. The grey precipitate was filtered and the solid was purified by chromatography (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g+12 g stack silica gel columns) to give 485 mg of (R)-tert-butyl-1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate as a yellow solid.
Reaction SMILES: [N+:1]([CH:4]([CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-])=O.O.[ClH:26]>C(O)C.[Pd]>[ClH:26].[NH2:1][CH:4]([CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C1c2ccccc2C=Cc2ccccc21)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(N)C1c2ccccc2CCc2ccccc21

Procedure:
Ethyl α-nitro-5H-dibenzo[a,d]cycloheptene-5-acetate (13 g, 40 mmol) (Example 4, Step A) is dissolved in 150 mL of ethanol, 40 mL of water, and 3.5 mL of concentrated hydrochloric acid and hydrogenated with 2.0 g of 20% palladium on carbon (52 psi, 30 hours). The filtered solution is stripped and a white solid washed with diethyl ether, dried at 50° C./2 mm Hg. The crude product is used as is in the next step.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:27]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)/[CH:28]=[C:29](\[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])/[CH3:30]>C(O)C>[ClH:1].[ClH:1].[CH2:27]([N:37]1[CH2:38][CH2:39][N:40]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:41][CH2:42]1)/[CH:28]=[C:29](\[CH2:31][CH2:32][CH:33]=[C:34]([CH3:35])[CH3:36])/[CH3:30]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CC(C)=CCC/C(C)=C\CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)=CCC/C(C)=C\CN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Product: Cl
Yield: 65 %

Procedure:
5,11-Dihydro-11-[(4-neryl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one dihydrochloride was prepared from 5.8 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one, 2.4 gm of sodium carbonate and 5.3 gm of 1-neryl-piperazine in 100 ml of absolute ethanol in analogy to Example 1. The obtained raw product was purified on a silica gel column and converted into the dihydrochloride in absolute ethanol with concentrated hydrochloric acid. After recrystallization from absolute ethanol: M.p.: 188°-191° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:14]=1.C(O)(=O)C>COC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Agent: COC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
NaH (155 mg) was added to a solution of 4-methoxy-phenol (500 mg) in dimethyl ether (DME) (2 ml) and stirred for 1 hour. (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added to the mixture, and the mixture was heated at 150° C. for 30 minutes under microwave irradiation. The reaction mixture was acidified to pH=7 with acetic acid and purified by preparative LC-MS to give [1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (30 mg). LC-MS: m/e 347(MH+). 1H NMR(CDCl3): δ 2.18(s, 3H), δ 3.85(s, 3H), δ 5.64(s, 1H), δ 6.78(s, 1H), δ 6.87(s, 1H), δ 7.02(m, 2H), δ 7.21(m, 3H), δ 7.31(m, 1H), δ 7.54(d, 2H), δ 8.27(d, 1H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Cl-].[Ca+2].[NH2:9][C:10]1[C:11](=[O:26])[NH:12][CH:13]=[C:14]([CH3:25])[C:15]=1[S:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:25][C:14]1[C:15]([S:16][C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)=[C:10]([NH:9][C:1](=[O:4])[CH2:2][CH3:3])[C:11](=[O:26])[NH:12][CH:13]=1
Reactant: Cc1cc(C)cc(Sc2c(C)c[nH]c(=O)c2N)c1
Reactant: CCC(=O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1c(Sc2cc(C)cc(C)c2)c(C)c[nH]c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
Freshly distilled propionyl chloride (0.04 ml, 0.41 mmole) (the receptacle is fitted with a trap containing CaCl2) was added to a solution of amine 8a (0.10 g, 0.40 mmole) and triethylamine (0.04 ml, 0.38 mmole) in dichloromethane (5 ml) at 0° C. The mixture was agitated at ambient temperature for 5 hours. The solvent was evaporated, water was added and the solid was isolated by filtration. The residue was purified by column chromatography using a mixture of dichloromethane and ethanol (94:6) as eluant and at the end ethyl acetate in order to obtain the compound 11c (0.10 g, 90%) in the form of a white powder: melting point 186-188° C.; NMR-1H (DMSO-d6) δ 11.86 (1H, s, NH-1), 8.60 (1H, s, NH-3), 7.21 (1H, s, H-6), 6.88 (1H, s, H-4'), 6.80 (2H, s, H-2' and 6'), 4.04 (2H, q, J=7 Hz, COCH2CH3), 2.22 (6H, s, CH3 -3' and 5'), 1.82 (3H, s, CH3 -5), 1.20 (3H, t, J=7 Hz, COCH2CH3). Anal. C17H20N2O2S . 1.25H2O (C, H, N, S).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, 4-bromoaniline (15.75 g, 91.6 mmol) was dissolved in anhydrous dichloromethane (220 ml) in a 500-ml flask. Triethylamine (14.1 ml, 100 mmol) was added to the solution. The mixture was cooled in an ice bath and 3-(trifluoromethyl)benzoyl chloride (21 g, 100 mmol) was added slowly through a syringe. The reaction mixture was allowed to warm to room temperature with stirring overnight. Deionized water was added to the mixture and the solution was transferred to a separatory funnel. The organic layer was separated and washed one more time with deionized water. The water was discarded, and the organic layer contained a suspension that was collected and heated to 40° C. to afford dissolution. After cooling to room temperature, a solid formed. The solid was collected by filtration and was triturated in dichloromethane (100 ml). The solid was then filtered and dried under high vacuum oven at 65° C. Pure product was obtained (28 g, 90% yield). M/Z of [M−H]−=343. 1H NMR (DMSO) δ=7.6 (2H), 7.8 (3H), 7.95 (1H), 8.3(1H), 10.6 (1H).