Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC=CCO.[H-].[Na+].[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26](F)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1.C(O)(=O)[CH2:35][C:36]([CH2:41]C(O)=O)([C:38](O)=[O:39])O>CC(N(C)C)=O>[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([O:39][CH2:38][C:36]([CH3:41])=[CH2:35])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=C(C)COc1ccc([N+](=O)[O-])c(C(=O)Nc2cc(C(=O)NC3CC3)ccc2C)c1
Reaction time: 1 h

Procedure:
To a solution of methylallyl alcohol (3.6 ml) in anhydrous DMA (200 ml) was added sodium hydride (60% dispersion in oil, 6.7 g) and the solution stirred for 1 hour. N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide (10 g) was added and the mixture stirred at room temperature for 18 hours. The mixture was poured into 1N citric acid (300 ml) and the precipitated solid filtered off under reduced pressure and dried in the vacuum oven to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(2-methylprop-2-en-1-yl)oxy]-2-nitrobenzamide as an orange solid (8.73 g); NMR Spectrum (DMSOd6) 0.6 (m, 2H), 0.7 (m, 2H), 1.9 (s, 3H), 2.3 (s, 1H), 2.9 (m, 1H), 4.7 (s, 2H), 5.1 (s, 1H), 5.2 (s, 1H), 7.2 (m, 3H), 7.6 (d, 1H), 7.9 (s, 1H), 8.2 (d, 1H), 8.4 (m, 1H), 10.1 (s, 1H); Mass Spectrum: M+H+ 408.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([CH2:24][OH:25])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[N:11]1([C:14]2[N:15]=[CH:16][C:17]([CH2:24][OH:25])=[CH:18][C:19]=2[C:20]([F:23])([F:21])[F:22])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(CO)cc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Product: OCc1cnc(N2CCNCC2)c(C(F)(F)F)c1

Procedure:
4-(5-Hydroxymethyl-3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (d) above (1.08 g, 3.0 mmol) reacted with TFA (10 mL, Aldrich) under the conditions of Example 183 g to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 262 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[C:18]([O:20]C)=[O:19].[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=1.[OH-].[Na+]>[N+](C1C=CC=CC=1)([O-])=O.[Cu].C(O)C.O>[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[C:18]([OH:20])=[O:19])=[C:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=1
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Reactant: CCCCCCc1cc(SC)ccc1O
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCCCCCc1cc(SC)ccc1Oc1ccc(C(=O)O)cc1C(=O)O
Temperature: 140 °C
Yield: 74.7 %

Procedure:
0.4 g of copper powder and 5.5 g (0.04 mole) of potassium carbonate were added to a solution of 5.5 g (0.02 mole) of dimethyl 4-bromoisophthalate and 4.5 g (0.02 mole) of 4-methylthio-2-(n-hexyl)-phenol in 40 ml of nitrobenzene and the mixture was heated under a nitrogen atmosphere at 140° C for 3 hours and then was cooled. A solution of 3.2 g (0.08 mole) of sodium hydroxide in 60 ml of a 3-1 ethanol-water mixture was added thereto and the mixture was refluxed for 1 hour and then was poured into ice water. The mixture was extracted 3 times with dichloromethane and the aqueous phase was acidified with dilute hydrochloric acid and was filtered. The recovered solid was crystallized from methanol to obtain 5.8 g of 4-[4'-methylthio-2'-(n-hexyl)-phenoxy]-isophthalic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1>[Cl-].[Cl-].[Cl-].[Ti+3]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3cc(Cl)ccc3Cl)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(CN2CCN(c3cc(Cl)ccc3Cl)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(2,5-dichlorophenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(2,5-dichlorophenyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)(O[C:14]([CH3:18])([CH3:17])[C:15]#[CH:16])OC.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:17][C:14]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([CH3:18])[C:15]#[CH:16]
Reactant: C#CC(C)(C)OC(=O)OC
Reactant: N#Cc1ccc(O)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 23 h

Procedure:
To a solution of 4-cyanophenol (3.0 g, 25.18 mmol) and methyl 1,1-dimethyl-2-propynyl carbonate (3.93 g, 27.64 mmol) in anhydrous acetonitrile (24 mL) at 0° C. under argon was added DBU (5.0 mL, 33.43 mmol). After the solution had cooled to ~0° C., cupric chloride dihydrate (14.6 mg, 0.086 mmol) was added. After stirring at ~0° C. for 23 hours, the mixture was concentrated at reduced pressure. The residue was partitioned between 1N HCl (44 mL) and toluene (200 mL). The organic fraction was washed with 1N HCl (2×40 mL), 1N NaOH (2×40 mL), 1N NaHCO3, and brine. After drying (magnesium sulfate), the solvent was removed at reduced pressure to give crude title compound as a pale yellow oil. Distillation of the crude material (bulb to bulb) afforded the title compound as a colorless, low melting solid (4.05 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([S:18]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[N:1])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#CCCCCCCCCN
Solvent: c1ccncc1
Product: N#CCCCCCCCCNS(=O)(=O)c1ccccc1
Reaction time: 18 h
Yield: 19.4 %

Procedure:
A solution of 9-aminononanenitrile (2.0 g) in pyridine (60 ml) was treated with benzenesulphonyl chloride (2.29 g) in pyridine (10 ml). The solution was stirred for 18 hours when the solvent was removed in vacuo. The residue was dissolved in dilute hydrochloric acid and extracted with chloroform. The chloroform extract was dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (0.74 g) as a low melting solid.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH:13]=[CH:14][OH:15])=[C:10]([Cl:16])[N:9]=[C:8]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.[C:23]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>C(Cl)(Cl)Cl.CCOCC>[C:26]([C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH:13]=[CH:14][OH:15])=[C:10]([Cl:16])[N:9]=[C:8]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:21][CH:22]=1)=[O:33])([OH:28])=[O:27]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCCc1nc(Cl)c(CC=CO)n1Cc1ccc(NC(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 95 mg of 3-[1-(4-aminobenzyl)-2-butyl-4-chloroimidazol-5-yl]propen-1-ol in 2 mL of CHCl3 was added 45 mg of phthalic anhydride and the mixture was stirred at room temperature for 1 hour. During this period of time the initially clear solution became turbid and produced solid. The reaction mixture was diluted with 2 mL of ether and the solid was collected by filtration and washed with ether. The desired product was obtained as a tan solid, 115 mg, m.p. 150°-151°; NMR (10% DMSO-d6 /CDCl3): δ 9.94 (s, 1 h); 7.71 and 6.93 (d, 4H, J=8.3 Hz); 6.36 (m, 2H); 5.1 (s, 2H); 4.18 (d, 2H, J=3.9 Hz); 2.6 (t, 3H, J=7.4 Hz); 1.68 (m, 2H); 1.34 (m, 2H); 0.89 (t, 3H, J=7.4 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:2]1.C1C(=O)N([Br:23])C(=O)C1>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[Br:23])[CH3:15]
Reactant: CCOC(=O)Cc1c[nH]c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)Cc1c(Br)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
To a solution of 15.0 g (73.8 mmol) of ethyl (indol-3-yl)acetate in 75 ml of anhydrous dichloromethane at 0° C. was added 13.1 g (73.8 mmol) of NBS in small portions. The mixture was stirred at 0° C. for 3 h and then quickly concentrated under reduced pressure (argon was used to normalize the pressure after concentration to avoid decomposition due to the product's instability). Column chromatography with 99:1 toluene/ethanol afforded 10.5 g (50%) of the 2-bromoindole as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].F[B-](F)(F)F.[CH3:17][O+](C)C.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:11])[N:6]([CH3:17])[N:7]=2)[CH:3]=1
Reactant: C[O+](C)C
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1c2cc(Br)ccc2nn1C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
To a solution of 5-bromo-3-methyl-1H-indazole (4.25 g) in ethyl acetate (100 ml) was added trimethyloxonium tetrafluoroborate (4.47 g) at room temperature, and the mixture was stirred at the same temperature for 5 hr. To the obtained reaction mixture was added 1 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.65 g).
Reaction SMILES: CO.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:14][C@H:13]2[C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:7]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]2[CH2:14][C@H:13]2[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reaction time: 5 h
Yield: 33 %

Procedure:
To a 1000 mL parr hydrogenater flask with methanol (70 mL) and ethyl acetate (70 mL), was added methyl (1R,2R)-2-(4-nitrophenyl)cyclo propane carboxylate (14 g, 63.3 mmol) and 10% Pd/C (2 g) under N2 atmosphere. The RM was hydrogenated at 40 psi for 5 h. RM was diluted with ethyl acetate (100 mL), filtered through celite bed to remove Pd/C and evaporated to dryness under reduced pressure. The crude was purified by flash column chromatography on silica gel (230/400 mesh), to give the product (4 g, yield: 33.1%). MS (ESI, 120 eV): m/z=192.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 6.83-6.86 (d, 2H), 6.58-6.61 (d, 2H), 3.63 (s, 3H), 2.36-2.39 (m, 1H), 1.69-1.75 (m, 1H), 1.42-1.49 (m, 1H), 1.14-1.20 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C:3]2([CH2:10][CH:9]3[CH2:11][N:6]2[CH2:7][CH2:8]3)[CH2:2]1.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N:1]2[CH2:5][CH2:4][C:3]3([CH2:10][CH:9]4[CH2:11][N:6]3[CH2:7][CH2:8]4)[CH2:2]2)[CH:14]=1
Reactant: C1CC2(CN1)CC1CCN2C1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cncc(N2CCC3(CC4CCN3C4)C2)c1
Temperature: 0 °C
Yield: 77.1 %

Procedure:
A mixture of spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] (300 mg, 1.98 mmol), 3-bromopyridine (344 mg, 2.18 mmol), tris(dibenzylideneacetone)dipalladium(0) (54.57 mg, 0.0654 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (74.22 mg, 0.131 mmol) and potassium tert-butoxide (668.8 mg, 5.96 mmol) in dry toluene (20 mL) was heated in a sealed tube flushed with argon gas at 90° C. for 8 h. The reaction was cooled to 0° C. and the contents transferred to a 100 mL round bottom flask. The solvent was removed by rotary evaporation and the residue was dissolved in a saturated solution of NaHCO3 (10 mL) and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated by rotary evaporation to give a dark colored syrup. This was purified by column chromatography, using MeOH:CHCl3:NH4OH (8:2:0.01, v/v) as the eluent, to afford 350 mg (79.0%) of 1′-(3-pyridyl)-spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine] as a light brown syrup. A portion of the free base (200 mg) was converted to a hydrochloride salt, which was crystallized from isopropanol and ethanol to yield 200 mg (76%) of a light brown solid, (m.p. 232°-236° C.).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][CH2:21][O:22]C3CCCCO3)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][CH2:21][OH:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(OCCOC2CCCCO2)c2ccc(F)cc12
Solvent: CO
Product: O=c1[nH]c(-c2ccccc2)c(OCCO)c2ccc(F)cc12
Temperature: 55 °C
Yield: 95 %

Procedure:
To a solution of 590 mg (1.54 mmol) of 7-fluoro-3-phenyl-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]isoquinolin-1(2H)-one in methanol (12 mL), 88 mg of p-toluenesuphonic acid (0.46 mmol) were added and the resulting mixture was heated at 55° C. for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed twice with aqueous sodium hydrogencarbonate saturated solution. The combined organic layer were dried over sodium sulphate and concentrated under reduced pressure to afford 438 mg of the title compound (95%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=3)[C:11]([CH:21]=[CH2:22])=[N:10]2)[CH:5]=[CH:4][CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[CH2:21]([C:11]1[C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][C:17]=2[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[N:10]=1)[CH3:22]
Reactant: C=Cc1nn(Cc2cccc(C)n2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(N)c12
Yield: 97.5 %

Procedure:
A mixture of 1-((6-methylpyridin-2-yl)methyl)-4-nitro-3-vinyl-1H-indazole (161 mg, 0.547 mmol) and 20% palladium hydroxide on carbon (38.4 mg, 0.0547 mmol) was stirred in methanol (3 mL) under an atmosphere of hydrogen for 3 hours. The mixture was diluted with methanol and filtered through glass fiber filter paper. The filtrate was concentrated under reduced pressure to give 3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (142 mg).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+].C(O)C>O.Cl>[C:20]1([NH:26][N:27]=[C:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([C:13]([NH2:15])=[O:14])[C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[CH2:3]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNc1ccccc1
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)N1c2ccccc2CC(=NNc2ccccc2)c2ccccc21
Temperature: 60 °C

Procedure:
A mixture of 0.2 g (0.8 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, 0.5 g (4.6 mmol) of phenylhydrazine and 0.5 g (6 mmol) of sodium acetate in a mixture of 5 mL of water, 5 mL of ethanol and 3 drops of concentrated hydrochloric acid was heated at 60° C. for thirty minutes and then allowed to cool to room temperature. The precipitate was then filtered and washed with cold water and dilute ethanol to give the desired product as yellow crystals of m.p. 220° to 220.8° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[C:37]([Sn](CCCC)(CCCC)CCCC)[S:38][C:34]=2[CH:33]=[N:32]1.[F-].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([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)=CC=1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:19]([N:17]2[CH2:18][C@H:14]([C@H:12]([O:11][C:4]3[C:5]4[N:6]([N:8]=[CH:9][CH:10]=4)[CH:7]=[C:2]([C:37]4[S:38][C:34]5[CH:33]=[N:32][N:31]([CH3:30])[C:35]=5[CH:36]=4)[CH:3]=3)[CH3:13])[CH2:15][C:16]2=[O:29])[CH3:20])=[CH:22][CH:23]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4nccc34)CC2=O)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cnn2C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4cc5c(cnn5C)s4)cn4nccc34)CC2=O)cc1
Temperature: 50 °C

Procedure:
A solution of (R)-4-((R)-1-((6-bromopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.01 (30 mg, 0.065 mmol) and 1-methyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (36 mg, 0.085 mmol, prepared according to protocols described in WO2012/177714 and US2012/043276) were dissolved in DMF (0.6 mL). Cesium fluoride (20 mg, 0.13 mmol), cuprous iodide (2.5 mg, 0.013 mmol) and Pd(PPh3)4 (7.6 mg, 0.0066 mmol) were added. Argon gas was bubbled through the reaction mixture for 2 minutes and the reaction was heated to 50° C. for 16 h. The reaction was cooled to room temperature, EtOAc and water were added, the layers were separated and the aqueous layer was extracted with EtOAc (1x). The combined organics were washed with water, dried (MgSO4), filtered and concentrated to a residue which was purified by silica gel chromatography (0-5% MeOH in EtOAc) to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((R)-1-((6-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 6.28.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][O:10][C:9]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[O:17][C:16]([CH3:26])([CH3:25])[CH2:15][CH2:14][C:13]=3[C:12]2=[O:27])[O:8]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C.C(Cl)Cl>[N:28]([CH2:6][CH:7]1[CH2:11][O:10][C:9]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[O:17][C:16]([CH3:26])([CH3:25])[CH2:15][CH2:14][C:13]=3[C:12]2=[O:27])[O:8]1)=[N+:29]=[N-:30]
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(COS(C)(=O)=O)O1)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CN=[N+]=[N-])O1)C2=O
Temperature: 100 °C
Yield: 14.6 %

Procedure:
To a solution of 4′-(hydroxymethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (316 mg, 1.0 mmol) in dichloromethane (2 mL) is added methanesulfonyl chloride (0.095 mL, 1.3 mmol) and triethylamine (0.163 mL, 1.24 mmol). The mixture is stirred at room temperature for 2 hours. The reaction mixture is washed with water (2×1.0 mL), dried over sodium sulfate and concentrated to provide (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate as a white solid (99% by LC/MS, UV 254 nm). The (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate (197 mg, 0.5 mmol) is dissolved in DMF (2 mL) followed by the addition of sodium azide (97 mg, 1.5 mmol). The reaction is heated at 80° C. for 24 hour and 100° C. for 12 h. The mixture is diluted with CH2Cl2 (4 mL), washed with water (2 ml) and concentrated. The organic layer is dried with sodium sulfate, concentrated under reduced pressure and purified by flash column chromatography (SiO2, 30% EtOAc in hexane) to provide 4′-(azidomethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (25 mg, 15%) as a white solid. 400 MHz 1H NMR (CDCl3) δ: 7.78-7.56 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.40 (m, 2H), 4.68-4.62 (m, 1H), 4.46-4.42 (m, 1H), 4.23 (t, J=8 Hz, 1H). 3.96-3.91 (m, 1H), 3.54-3.49 (m, 1H), 2.48-2.42 (m, 2H), 1.79 (t, J=6.8 Hz, 2H), 1.42 (d, J=3.2 Hz, 6H); LCMS: 342 [M+H].
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH:24]1[O:28][CH2:27][CH2:26][O:25]1.O>CN(C=O)C>[O:25]1[CH2:26][CH2:27][O:28][CH:24]1[CH2:23][N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CC3OCCO3)c(=O)c2c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 64.3 %

Procedure:
To a solution of methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.5 g, 1.72 mmol) in DMF (10 mL) was added potassium carbonate (1.2 g, 8.6 mmol) and 2-(bromomethyl)-1,3-dioxolane (0.62 mL, 6.03 mmol). The reaction mixture was heated at 140° C. and stirred for 5 h. The mixture was cooled to rt, water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-(1,3-dioxolan-2-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.32 g, 64%). LC-MS: (FA) ES+ 290.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([Br:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc(Br)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Temperature: 190 °C
Reaction time: 2.5 h

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (167 mg, 0.87 mmol) (described in a previous experimental) and 3-bromoaniline (0.75 mL, 7.8 mmol) is stirred under N2 at 190° C. for 2.5 h, and the precipitate which appears on cooling is recrystallized from PriOH. 1H NMR (DMSO) δ 9.91 (1H, brs), 9.34 (1H, s), 8.45 (1H, s), 8.19 (1H, s), 7.84 (1H, d, J=8.0 Hz), 7.34 (1H, t, J=8.0 Hz), 7.29 (1H, d, J=8.2 Hz), 6.68 (2H, brs), 6.45 (1H, s).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>[Ni].CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([Cl:28])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(CNC(=O)c2cccc(Cl)c2)c(NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-chlorobenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, with the exception that Raney nickel and TEA in methanol was used for the hydrogenation step, to give Example 64. ESI-MS m/e 361.5 (M+1).