Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:25].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22][O:23][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC1CN(c2ccccc2C)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred, 0° C. solution of 1-t-butyloxycarbonyl-2-(2-hydroxyethyl)-4-(2-methylphenyl)piperazine from Step 1 above (0.38 g; 1.2 mmol) and iodomethane (0.20 mL; 3.4 mmol) in dry THF (20 mL) was added NaH (60 mg of a 60% suspension in mineral oil; 1.5 mmol). The reaction was stirred at 0° C. for 15 min and then at ambient temperature for 18 h. The reaction was quenched by adding several drops of MeOH and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The organic phase was separated and washed with water and brine. The s organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc:hexanes as eluant. The title compound was obtained as a gum (1H-NMR: consistent with structure; TLC: silica gel, 1:3 EtOAc:hexanes: single component, Rf =0.62; FABMS: M+ H @ m/e=335; HPLC: >99%, retention time 11.7 min).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13].[Cl-].[Li+].[F-].[K+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(OCC)C.C(OCC)(=O)C>[CH:12]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)=[CH2:13]
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: C=Cc1ccc2c(c1)NC(=O)C2
Yield: 31.4 %

Procedure:
To a mixture of 6-bromooxindole (Procedure D, 0.50 g, 2.4 mmol), vinyltributylstannane (0.95 g, 3.0 mmol), lithium chloride. (03 g, 7.1 mmol), 2,6-di-tert-butyl-4-methylphenol (0.01 g, 0.05 mmol) in acetonitrile (25 ml) stirring at 80° C. was added dichlorobis(triphenylphosphine)palladium (II). The resulting reaction was stirred with heating for 16 h. The reaction was poured into a vigorously stirring mixture of 5M potassium fluoride solution: ethyl acetate/1:1 (250 mL) and stirred for 0.75 h. The resulting biphashic mixture was filtered through a Celite 521 pad and the pad flushed with ethyl acetate (5×200 mL). The combined organic phases were washed with water (200 mL), saturated sodium chloride (200 mL) and filtered through Whatman PS 1 paper and evaporated in vacuo to a golden yellow syrup. The syrup was titurated with diethyl ether to yield several crops of tan solid. Pure samples were combined, slurried with diethyl ether, filtered, and air dried to yield 0.12 g (31%) of 6-vinyloxindole: 1H NMR (DMSO-d6): δ10.36 (s,1H), 7.13 (d,1H, J=7.7 Hz), 6.98 (d,1H, J=7.5 Hz), 6.66 (dd,1H, J=10.9,17.7 Hz), 5.70 (d,1H, J=17.6 Hz), 5.18 (d,1H, J=10.9 Hz), 3.42 (s,2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:26])=[C:18]([CH:25]=1)[C:19](N(OC)C)=[O:20]>O1CCCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:26])=[C:18]([C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:20])[CH:25]=1
Reactant: CON(C)C(=O)c1cc(Br)ccc1F
Reactant: Brc1ccccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ccccn1)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An oven-dried flask was cooled under argon, then charged with anhydrous THF (40 mL) and 2-bromopyridine (1.76 mL, 18 mmol). Isopropylmagnesium chloride in tetrahydrofuran (2.0 M in THF, 11 mL) was then added dropwise at room temperature. The mixture was then stirred at room temperature for 2 hours, then cooled to 0° C., whereupon a THF solution (5 mL) of 5-bromo-2-fluoro-N-methoxy-N-methylbenzamide (3.93 g, 15 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with saturated NH4Cl, extracted with EtOAc, washed with 10% HCl, dried over Na2SO4, and purified by column chromatography (gradient 0 to 10% EtOAc/hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J=4.6 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.79 (dd, J=5.8, 1.4 Hz, 1H), 7.67-7.59 (m, 1H), 7.52 (dd, J=7.4, 4.9 Hz, 1H), 7.04 (t, J=9.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[NH:13])[NH:11][OH:12])[CH:5]=[N:6][C:7]=1[S:8][CH3:9].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=O>C1(C)C=CC=CC=1>[C:15]([C:20]1[O:12][N:11]=[C:10]([C:4]2[CH:5]=[N:6][C:7]([S:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)([CH3:19])([CH3:16])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CSc1ncc(C(=N)NO)cc1Cl
Solvent: Cc1ccccc1
Product: CSc1ncc(-c2noc(C(C)(C)C)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
5-Chloro-6-methylthio-N-hydroxy-3-pyridinecarboximidamide (1.0 g, 4.6 mmol) was slurried in toluene (20 mL) and trimethylacetyl chloride (0.61 g, 5.1 mmol) added. The mixture was stirred at room temperature for one hour and then heated under reflux conditions for four hours. This was then cooled and filtered through Celite, washing with additional toluene (20 mL). Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (0-10% ethyl acetate:hexane) gave the desired product as a white solid (0.77 g, 59%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][N:14]2[C:20](=[O:29])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:12])=[CH:6][CH:5]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:20]([N:14]2[CH2:15][C@H:16]([O:18][CH3:19])[CH2:17][C@@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][CH:6]=2)=[O:12])=[O:29])=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2C(=O)Nc2ccc(Cl)cc2)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@H](C(=O)Nc2ccc(C(=O)O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
Into a solution of 9 (3.0 g, 6.94 mmol) in THF (50 mL) was added potassium trimethylsilanolate (3.85 g, 27.3 mmol). The solution was stirred at RT for 48 h before concentrating under reduced pressure and adding EtOAc. The solution was washed sequentially with 1N HCl, and brine, before drying over MgSO4 and concentrating under reduced pressure to give 10 (2.9 g, 100%). MS: APCI (AP+): 418.1 (M)+, (AP−): 416.1 (M)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][NH:21][N:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[C:19]3[N:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: COc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1
Yield: 59.4 %

Procedure:
Reaction of 1-(4-methoxy-phenyl)-4,4,4-trifluoro-butane-1,3-dione (123 mg, 0.5 mmol), prepared from commercially available 4-methoxy-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (110 mg, 59%). MS (ISP) 371.2 [(M+H)+]; mp 244° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C)P(=O)(N(C)C)N(C)C>[C:14]1([NH:20][C:21](=[S:22])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccccc2)n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5 g of ethyl 2-aminothiazol-4-ylglyoxylate were dissolved in 30 ml of hexamethylphosphoric triamide, and 5.2 g of phenyl isothiocyanate were added to the resulting solution under ice-cooling. The reaction mixture was kept stirred at an external temperature of 60° C. for 8 hours, then acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crystals which precipitated out were collected by filtration to give the desired compound as pale yellow crystals.
Reaction SMILES: Cl.[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([NH:36][CH2:37][CH2:38][F:39])[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]>O1CCOCC1>[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:36][CH2:37][CH2:38][F:39])[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NCCF
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C(=O)O)c(NCCF)c2)cn1
Temperature: 100 °C
Yield: 34.6 %

Procedure:
1.54 ml of 1N hydrochloric acid are added to a solution of 0.13 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(2-fluoroethyl)amino]benzoate in 6 ml of dioxane. The reaction mixture is heated at 100° C. in a microwave for 2 hours and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (97/3 by volume), so as to give 40 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(2-fluoroethyl)amino]benzoic acid in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[Na+].O.[Cl:11][CH2:12][C:13]([N:15]([CH2:24]Cl)[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23])=[O:14]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[Cl:11][CH2:12][C:13]([N:15]([CH2:24][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=[CH:4]1)[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23])=[O:14]
Reactant: Cc1cccc(C)c1N(CCl)C(=O)CCl
Reactant: Clc1nc[nH]c1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C)c1N(Cn1cnc(Cl)c1Cl)C(=O)CCl
Reaction time: 2 h

Procedure:
A solution of 13.7 parts by weight of 4,5-dichloroimidazole and 4.4 parts by weight of sodium hydroxide in 20 parts of water was added dropwise to a solution of 24.6 parts by weight of 2-chloro-N-chloromethyl-2',6'-dimethylacetanilide and 2.0 parts by weight of triethylbenzylammonium chloride in 50 parts by volume of dichloromethane at 20°-25° C., with vigorous stirring, which was continued for 2 hours. The organic phase was washed with three times 30 parts by volume of water, dried over sodium sulfate and evaporated under reduced pressure at 70° C., to give 29.9 parts by weight of 2-chloro-2',6'-dimethyl-N-(4,5-dichloroimidazol-1-yl-methyl)-acetanilide of melting point 99° C.; the product was pure according to the 1H-NMR spectrum and according to thin layer chromatography carried out with a 3:7 ethyl acetate:toluene mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:10]=1[O:11][CH3:12])[C:5]([Cl:27])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)cc(C(=O)O)cc1OC(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(C(=O)Cl)cc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 13 h

Procedure:
To 3-chloro-4-methoxy-5-trifluoromethoxybenzoic acid (401 mg), toluene (4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) were added, and then the mixture was stirred at 60° C. for 13 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (436 mg) as a brown oily substance.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]=[C:9]=[CH:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[C:14]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8]/[CH:9]=[CH:10]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(O)C=C=C=C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/C=C(c1ccccc1)c1ccccc1)NCCCCc1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.4 %

Procedure:
To a stirred solution of 5,5-diphenyl-2,4-pentadienenoic acid (6.00 g) and triethylamine (3.7 mL) in dry tetrahydrofurane (40 mL) at 0°- C. was added a solution of ethyl chloroformate (2.37 mL) in tetrahydrofurane (15 mL) dropwise such that the reaction temperature was maintained at 0° C. After the addition was complete, the reaction was stirred at 0° C. for 15 minutes, then a solution of 3-pyridinebutanamine (3.78 g) in tetrahydrofurane (20 mL) was added dropwise while keeping the reaction at 0° C. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours before the precipitated triethylamine hydrochloride was removed by filtration. The evaporated filtrate was partitioned between 1N hydrochloric acid solution (80 mL) and ether (80 mL). After the ethereal extract was discarded, the aqueous layer was basified with 4N sodium hydroxide (30 mL) and extracted with ether (4×100 mL). Evaporation of the dried (K2CO3) organic extracts afforded the crude amide which was purified by HPLC (hexane-ethyl acetate-triethylamine; 25:75:2) to provide 3.55 g of (E)-5,5-diphenyl-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide 0.2 molar hydrate as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[NH:12][C:11]3=[O:17])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH2:15][CH:14]2[C:13](=[O:16])[NH:12][C:11]3=[O:17])=[CH:8][CH:9]=1
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C23CC2C(=O)NC3=O)cc1

Procedure:
To a solution of 25.9 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (preparation as described in DE-OS 2 740 562) in 700 ml of ethanol are added 1.4 g of 5% palladium/carbon catalyst. Hydrogenation is carried out under normal pressure and at room temperature with hydrogen. When the absorption of hydrogen is complete (theoretical amount: 7500 ml), the reaction mixture is diluted with 1 ml of ethanol and concentrated after removal of the catalyst. The product so obtained is recrystallised from ethanol, affording the title compound with m.p. 183°-185° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:26]([OH:42])[CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]#[N:41])[CH2:30][CH2:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(Cl)Cl>FC(F)(F)C(O)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[N:14]([CH2:25][CH:26]([OH:42])[CH2:27][N:28]3[CH2:33][CH2:32][N:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]#[N:41])[CH2:30][CH2:29]3)[N:15]=2)=[CH:18][C:19]=1[CH3:24]
Reactant: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CNCC3)ccc1Cl
Reaction time: 2 h
Yield: 100.4 %

Procedure:
3-(4-Chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.26 g, 2.13 mmol) was dissolved in trifluoroacetic acid (3 mL) and CH2Cl2 (3 mL) and allowed to stir for 2 h. The reaction mixture was concentrated, taken up in EtOAc (50 mL) and washed with aqueous NaHCO3 (2×25 mL). The EtOAc layer was dried over Na2SO4 and concentrated to give 2-(4-{3-[3-(4-chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile (1.05 g, 99%) as a yellow foam. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.27. MS (electrospray): m/z 491.2 (491.2, calculated for C27H31ClN6O, [M+H]+). 1H NMR (400 MHz, CDCl3): 9.8 (br s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.11 (t, J=8.2 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 4.56 (br s, 1H), 4.12-4.32 (m, 4H), 2.98-3.51 (m, 13H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9](Cl)=[O:10])[C:4]([N+:12]([O-:14])=[O:13])=[N:3]1.[CH3:15][NH2:16]>C1(C)C=CC=CC=1>[CH3:15][NH:16][C:9](=[O:10])[CH:8]=[CH:7][C:5]1[C:4]([N+:12]([O-:14])=[O:13])=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: Cn1cc(C=CC(=O)Cl)c([N+](=O)[O-])n1
Reactant: CN
Solvent: Cc1ccccc1
Product: CNC(=O)C=Cc1cn(C)nc1[N+](=O)[O-]

Procedure:
0.54 g. 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid chloride (preparation see Example 2) is dissolved in 20 ml. anhydrous toluene and, while stirring at 25° C., methylamine gas is passed in for about 10 minutes. The precipitated crystals are filtered off with suction, washed with toluene, triturated with water and dried in a vacuum. There is thus obtained 0.43 g. 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid N-methylamide; m.p. 200°-203° C.
Reaction SMILES: F[B-](F)(F)F.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[N:16])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH2:17]([N:19]1[C:24]2[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1)[CH3:18].N>S(=O)(=O)(O)O>[CH2:17]([N:19]1[C:24]2[CH:25]=[C:26]([OH:29])[C:27]([N:16]=[N:15][C:12]3[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=3)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1)[CH3:18]
Reactant: CCN1CCOc2ccc(O)cc21
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Agent: F[B-](F)(F)F
Agent: N
Agent: O=S(=O)(O)O
Product: CCN1CCOc2cc(N=Nc3ccc([N+](=O)[O-])cc3)c(O)cc21

Procedure:
p-Nitrobenzenediazonium tetrafluoroborate (0.251 g, 1.06 mmol) was dissolved in 10% sulfuric acid (10 ml) and added to a methanolic solution (10 ml) of 50a (0.19 g, 1.06 mmol). The solution turned red immediately. The reaction mixture was neutralized with ammonia. The red precipitate was filtered to give quantitative yield of the product. ES-HRMS [M−H]− 327.1428. Calcd for (C16H15N4O4): 327.1094.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13].O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc(Br)cc1OC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 4-bromoveratrole (20 g) in acetic acid (50 ml) was added 2M nitric acid (48 ml). It was stirred at room temperature for 30 min and then the reaction solution was poured into water. The resultant solid was filtered, washed with water and dried in vacuum.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:16].[F:17][C:18]1[CH:23]=[C:22](B(O)O)[C:21]([F:27])=[CH:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC.O>[Cl:16][C:3]1[C:2]([C:22]2[C:21]([F:27])=[CH:20][N:19]=[C:18]([F:17])[CH:23]=2)=[N:7][C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: OB(O)c1cc(F)ncc1F
Reactant: Clc1ccc(NCC2CCOCC2)nc1Br
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(F)cn1
Temperature: 105 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (0.500 g, 1.64 mmol), 2,5-difluoropyridin-4-ylboronic acid (0.260 g, 1.64 mmol), and sodium carbonate (2.45 ml, 4.91 mmol, 2 M in H2O) were dissolved in DME (7.36 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf)CH2Cl2 adduct (0.267 g, 0.327 mmol). The reaction mixture was then heated in the microwave at 105° C. for 25 min. More boronic acid (0.260 g, 1.64 mmol) and PdCl2(dppf)CH2Cl2 adduct (0.267 g, 0.327 mmol), and H2O (˜2 ml) were added. Heating in the microwave was continued at 110° C. for 30 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated in vacuo to give 1.2090 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 10 EtOAc/90 heptane to 80 EtOAc/20 heptane gave 0.3584 g (65%) of 3-chloro-2′,5′-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine. LCMS (m/z): 340.0 (MH+), retention time=0.90 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.37 (qd, 3H) 1.60 (br. s., 2H) 1.68 (d, J=12.91 Hz, 3H) 1.84 (ddd, J=11.15, 7.24, 4.30 Hz, 1H) 3.21 (t, J=6.26 Hz, 2H) 3.32-3.45 (m, 3H) 4.00 (dd, J=11.15, 3.72 Hz, 2H) 4.74 (br. s., 1H) 6.45 (d, J=9.00 Hz, 1H) 6.99-7.07 (m, 1H) 7.51 (d, J=8.61 Hz, 1H) 8.12 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]([NH:13][CH:14]3[C:22]4[C:17](=[C:18]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl>CO>[NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]([NH:13][C@H:14]3[C:22]4[C:17](=[C:18]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(Nc1cccc2[nH]ncc12)NC1CCc2c1cccc2N1CCCCC1
Agent: Cl
Solvent: CO
Product: O=C(Nc1cccc2[nH]ncc12)N[C@@H]1CCc2c1cccc2N1CCCCC1

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound 1-(1H-Indazol-4-yl)-3-(4-piperidin-1-yl-indan-1-yl)-urea (Ex. 56E) using a chiral column ChiralCel OD. [α]D: +89.5° (HCl salt, c: 1.02, MeOH). MS (ESI) m/z: 376.00 [M+H]+. 1H NMR (DMSO-d6) δ: 1.56 (m, 2H), 1.65 (m, 4H), 1.78 (m, 1H), 2.44 (m, 1H), 2.77 (m, 1H), 2.85 (m, 3H), 2.95 (m, 2H), 5.16 (q, 1H), 6.66 (d, 1H), 6.81 (d, 1H), 6.95 (d, 1H), 7.07 (d, 1H), 7.22 (m, 2H), 7.68 (d, 1H), 8.05 (s, 1H), 8.62 (s, 1H), 13.00 (s, 1H). Anal Calcd for C22H25N5O: C, 70.38; H, 6.71; N, 18.65. Found: C, 70.45; H, 6.91; N, 18.00.