Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].C(OCC)(=O)C.[OH-].[Na+]>ClC1C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH:3]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)OC(=O)c1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 120 °C
Reaction time: 23 h
Yield: 45.3 %

Procedure:
2-Propyl 4-chloropyridine-2-carboxylate (3.13 g) was dissolved in chlorobenzene (9.5 ml). 4-Nitrophenol (3.28 g) was added thereto, followed by stirring at 120° C. for 23 hr. 4-Nitrophenol (1.09 g) was added thereto, followed by stirring at 120° C. for 3 hr. The reaction mixture was allowed to cool down to room temperature. Ethyl acetate (50 ml) and a 1N aqueous solution of sodium hydroxide (50 ml) were added to the reaction mixture and stirred. Insoluble matter was precipitated, which was dissolved by addition of THF (50 ml). The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide (50 ml×3) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1 to 1:1). Fractions containing the target compound were concentrated under reduced pressure, and dried under reduced pressure to provide the titled compound as pale brown crystals (2.147 g, 45%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=O)OC(=O)[C:5]2=[CH:11][C:12]=1F.[F:14][C:15]1[CH:16]=[C:17]([C:25]([OH:27])=[O:26])[C:18](=[CH:22][C:23]=1[F:24])C(O)=O.[CH3:28][C:29]([N:31](C)C)=O>CN1CCCC1=O>[N:31]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:12][CH:11]=2)[CH:9]=[CH:28][CH:29]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:22][C:23]=1[F:24])[C:25]([OH:27])=[O:26]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Reactant: CC(=O)N(C)C
Reactant: O=C(O)c1cc(F)c(F)cc1C(=O)O
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(F)c(F)c1
Product: c1ccc2ncccc2c1

Procedure:
Surprisingly, we have found that 4,5-difluorophthalic anhydride and 4,5-difluorophthalic acid may be selectively decarboxylated in N-methyl-pyrrolidone, dimethyl acetamide or quinoline to yield 3,4-difluorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:15]3[C:11]([S:12][C:13]([C:19]([N:21]4[CH2:41][C@H:40]([F:42])[CH2:39][C@H:22]4[C:23]([N:25]4[CH2:32][C:29]5([CH2:31][CH2:30]5)[N:28](C(=O)C(F)(F)F)[CH2:27][CH2:26]4)=[O:24])=[O:20])=[C:14]3[CH:16]([CH3:18])[CH3:17])=[N:10][C@:9]2([C:44]2[CH:45]=[N:46][C:47]([Cl:50])=[CH:48][CH:49]=2)[CH3:43])=[CH:4][C:3]=1[F:51].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:15]3[C:11]([S:12][C:13]([C:19]([N:21]4[CH2:41][C@H:40]([F:42])[CH2:39][C@H:22]4[C:23]([N:25]4[CH2:32][C:29]5([CH2:30][CH2:31]5)[NH:28][CH2:27][CH2:26]4)=[O:24])=[O:20])=[C:14]3[CH:16]([CH3:17])[CH3:18])=[N:10][C@:9]2([C:44]2[CH:45]=[N:46][C:47]([Cl:50])=[CH:48][CH:49]=2)[CH3:43])=[CH:4][C:3]=1[F:51]
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CCN(C(=O)C(F)(F)F)C3(CC3)C2)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CCNC3(CC3)C2)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Temperature: 40 °C
Yield: 55.1 %

Procedure:
The compound (390 mg, 0.51 mmol) obtained in Step 1 above was dissolved in 10% aqueous methanol (8 ml), potassium carbonate (400 mg, 2.89 mmol) was added and the resulting mixture was stirred under heating at 40° C. for 2 hours. The solvent was concentrated under reduced pressure and then the residue obtained was diluted with ethyl acetate, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=15:1 (v/v)] to give the title compound (190 mg, 55%) as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N:7][CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].C(O)(=[O:16])CC.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N+:7]([O-:16])[CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2]
Reactant: CCc1nc2nccc(C)c2[nH]1
Reactant: CCC(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c([nH]1)c(C)cc[n+]2[O-]

Procedure:
A solution of 28 g (174 mmol) of 2-ethyl-7-methylimidazo[4,5-b]pyridine prepared according to Example 2, Steps A and B, but substituting propionic acid in place of butyric acid in Step B (described in European Patent Application #400,974, May 12, 1990) and m-chloroperbenzoic acid (80-90%, 44.6 g) in CHCl3 (300 mL) was heated at reflux for 0.5 hours. The mixture was concentrated and purified (SiO2, 100% CH2Cl2 gradient to 30% CH2Cl2 /MeOH) to give 29.8 g of the title compound as a solid.
Reaction SMILES: C1C=CC(O[C:8](OC2C=CC=CC=2)=[N:9][C:10]#[N:11])=CC=1.[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:31]1>C(#N)C>[C:10]([NH:9][C:8]([N:20]1[CH2:21][CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19]1)=[N:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:31]1)#[N:11]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCNC2
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: N#CNC(=NC1CCN(Cc2ccccc2)CC1)N1CCc2ccccc2C1
Reaction time: 2 h

Procedure:
5 mmole of diphenylcyanocarbonimidate (M.W. 238) in 15 ml of acetonitrile was added to 5 mmole of 1,2,3,4-tetrahydroisoquinoline at room temperature. After four hours of stirring at room temperature 5 mmole of 4-amino-1-benzyl piperidine was added to the reaction and stirring continued for an additional 2 hours. The mixture was then placed in a high pressure environment (20,000 psi) for 17 hours. The solution was evaporated and the residue was separated and purified by column chromatography (toulene:ethylacetate:triethylamine, 40:60:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9]2)=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:17]1([CH:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:9]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1=C(c2ccccc2)c2ccccc2C1(Cc1ccncc1)Cc1ccncc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(C2CC(Cc3ccncc3)(Cc3ccncc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-bis(4-pyridinylmethyl)-3-phenyl-1H-indene (5.8 g, 15.5 mmol) in 95% ethanol (100 ml), was added 5% palladium on carbon catalyst (1.45 g) and the mixture was shaken under hydrogen (50 psig) at room temperature for 2 h. The catalyst was removed by filtration, and the solvent removed by rotary evaporation. The oil was purified via column chromatography (silica gel, 10% methanol/dichloromethane) to give pure 4-((2,3-dihydro-3-phenyl-1-(4-pyridinylmethyl)-1H-inden-1-ylmethyl))-pyridine. NMR (200 MHz, CDCl3) δ 2.05 (dd, 1H); 2.38 (dd, 1H); 2.93 (dd, 2H); 3.15 (dd, 2H); 3.42 (m, 1H); 6.67 (dd, 4H); 7.00 (d, 2H); 7.10-7.34 (m, 7H); 8.36 (d, 2H, J=5 Hz); 8.42 (d, 2H, J=5 Hz). Mass Calcd. for C27H24N2 : 376.1937. Found: 376.1951.
Reaction SMILES: Cl[CH2:2][C@H:3]1[CH2:7][C@H:6](Cl)[CH2:5][N:4]1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:19][NH2:20]>CO>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([N:4]2[CH2:5][C@H:6]3[CH2:7][C@@H:3]2[CH2:2][N:20]3[CH3:19])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H](Cl)C[C@@H]2CCl)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3C)cc1
Temperature: 110 °C
Yield: 90 %

Procedure:
A Parr bottle was charged with 0.5 g (1.29 :mmol) of (2R,4S)-2-chloromethyl-4-chloro-1-(4-toluenesulfonyl)pyrrolidine and 6 ml of methanol and the bottle was tared. Methylamine gas was then bubbled through the methanol solution until 0.4 g (12.9 mol) of the gas had dissolved. The bottle was then sealed and heated to 110° C. After heating for 16 hours, the reaction was cooled and the solvent was evaporated at reduced pressure. The residual solids were partitioned between 50 ml of methylene chloride and 40 ml of 10% aqueous NaOH solution. The layers were separated and the organic layer was washed with 40 additional milliliters of 10% aqueous NaOH solution, and then dried over Na2SO4. Evaporation of the solvent under reduced pressure provided 309 mg of the desired product which represents a 90% yield. M.P.=82°-87° C. [α]D =-16.8° (c=1.038, CH3OH).
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:7]2=[O:14].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O>>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:32])([F:20])[F:33])=[CH:27][CH:26]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:14])[N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[CH:5]=[CH:4]2
Reactant: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1N
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-amino-6-methoxy-1-oxoisoquinolin-2(1H)-yl)propanamide (98.34 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at room temperature overnight. The reaction was only 40% complete. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the pure product as a light yellow solid. MS m/z=448.3 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.71 (s, 1H), 8.17 (d, J=8.87 Hz, 1H), 7.74 (d, J=7.76 Hz, 2H), 7.62 (d, J=7.76 Hz, 2H), 7.34-7.29 (m, 2H), 7.20 (s, 1H), 6.28 (d, J=8.48 Hz, 1H), 5.45 (q, J=7.07 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 2H), 1.49 (d, J=7.39 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](Cl)=[O:26])[CH3:23].N1C=CC=CC=1.Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:22]([N:24]([CH2:28][CH3:29])[C:25]([O:12][C:11]1[CH:10]=[C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([N+:19]([O-:21])=[O:20])[C:2]=1[OH:1])=[O:26])[CH3:23]
Reactant: CCN(CC)C(=O)Cl
Reactant: COC(=O)c1c(-c2noc(C)n2)cc(O)c(O)c1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Oc1cc(-c2noc(C)n2)c(C(=O)OC)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrobenzoate (compound 1-5) (50 mg), diethylcarbamoyl chloride (0.024 mL), 4-dimethylaminopyridine (4 mg) and pyridine (2 mL) was stirred at room temperature for 3 hours. After addition of ethyl acetate, the mixture was acidified with 2 mol/L hydrochloric acid. The separated organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20%-100% ethyl acetate/hexane, gradient elution) to give the title compound (31 mg). The structural formula was illustrated in table 13.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(O)[CH2:6]2.C(O)(=O)C.Cl.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(OCC)C.CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH2:6]2
Reactant: Cc1ccc(C2(O)CC3CCC(C2)N3C)cc1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(C2=CC3CCC(C2)N3C)cc1

Procedure:
The title compound was prepared from 8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octan-3-ol (3.4 g, 14.7 mmol), glacial acetic acid (11 mL) and concentrated hydrochloric acid (11 mL). The free base of the title compound was dissolved in diethyl ether and added fumaric acid (1.3 g, 11.2 mmol) in methanol. The resulting solution was concentrated to dryness, the residue was trituated in diethyl ether, the title compound precipitated as powder and was isolated by filtration. Yield 2.46 g (51%) m.p. 156.8-157.4° C.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(Cl)(O[C:26](=[O:32])OC(Cl)(Cl)Cl)Cl.[CH3:34][NH:35][NH2:36]>ClCCCl>[CH3:34][N:35]([C:26]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:32])[NH2:36]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNN
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(N)C(=O)Nc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 50 %

Procedure:
2-Phenoxyaniline (5.57 g) and triethylamine (4.2 mL) were dissolved in 100 mL of 1,2-dichloroethane. Triphosgene (Cl3COC(=O)OCCl3, 2.97 g) was added and a precipitate formed. The mixture was heated to reflux and the solid redissolved. After 5.5 h, the solution was cooled and 1.6 mL of methyl hydrazine was added and a new precipitate formed. The mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between ethyl acetate and 1N aqueous HCl solution. The organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (1:1 hexane:ethyl acetate as eluant). The second-least polar component was collected, the eluant was removed under reduced pressure, and the residue was triturated with hexane to afford 3.86 g (50%) of the title compound of Step A, m.p. 117-119° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>>[F:10][C:4]1[CH:3]=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1F
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cc1F

Procedure:
The title compound was prepared by reacting 4-bromo-2-fluoroanisole (10 g, 0.049 mol) with n-butyl lithium (23.4 mL of 2.5 M solution in hexane, 0.059 mol) followed by triisopropyl borate (45.2 mL, 36.9 g, 0.196 mol) according to method F to yield 7.1 g (85.2%) of a white solid: MS (ESI) m/z 169 (M−H)−: 1H NMR (DMSO-d6): δ 3.84 (3H, s), 7.10–7.16 (1H, m), 7.51–7.60 (2H, m).
Reaction SMILES: Cl.[CH:2]([NH:5][CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)([CH3:4])[CH3:3].[CH2:27](Br)[CH:28]=[CH2:29].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:2]([N:5]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH2:29][CH:28]=[CH2:27])([CH3:3])[CH3:4]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCN(C(C)C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O

Procedure:
The mixture of 7.58 g of slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one hydrochloride, 4.8 g of allyl bromide, 5.5 g of potassium carbonate and 100 ml of anhydrous ethanol is refluxed for 3 hours. The mixture is recharged with 2.4 g of allyl bromide and 2.75 g of potassium carbonate and refluxed overnight. It is evaporated, water is added to the residue and the mixture extracted with chloroform. The extract is evaporated, the residue crystallized from petroleum ether and recrystallized from ethyl acetate to yield the 1-[2-(N-isopropyl-N-allylamino)propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, melting at 168°-170°.
Reaction SMILES: C(OC(=O)[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18](=[O:19])[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]#[N:34])=[C:23]([F:35])[CH:22]=3)=[C:16]([CH2:36][CH2:37][CH3:38])[N:15]3[N:39]=[CH:40][CH:41]=[C:14]23)[CH2:9][CH2:8]1)C.[CH3:43][Mg]Br.C([O:49][CH2:50][CH3:51])(=O)C>O1CCCC1>[F:35][C:23]1[CH:22]=[C:21]([CH2:20][C:17]2[C:18](=[O:19])[N:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][C:50]([OH:49])([CH3:51])[CH3:43])[CH2:8][CH2:9]3)[C:14]3[N:15]([N:39]=[CH:40][CH:41]=3)[C:16]=2[CH2:36][CH2:37][CH3:38])[CH:26]=[CH:25][C:24]=1[C:27]1[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reactant: C[Mg]Br
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of ethyl[(trans-4-{6-[(2′-cyano-2-fluorobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (0.33 g) in tetrahydrofuran (3 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 1.74 mL) at 0° C., and the mixture was stirred for 3 hr. To the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.23 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CN(c1cccc(-c2cccn3nc(N)nc23)c1)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5cccc(N(C)S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (67.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.033 g, 28%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.6, 1H), 8.13 (s, 3H), 7.93 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.4 Hz, 1H), 7.56-7.45 (m, 3H), 7.44 (dd, J=8.2, 1.2 Hz, 1H), 6.98-6.92 (m, 3H), 6.64 (s, 1H), 3.42 (s, 3H), 3.19-3.14 (m, 4H), 2.89 (s, 3H), 2.63-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: C1CCNCC1
Product: Nc1nnc(N2CCCCC2)c(-c2ccccc2)n1
Yield: 8.8 %

Procedure:
5-Phenyl-6-(piperidin-1-yl)-1,2,4-triazin-3-amine (18 mg, 18%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and piperidine (0.14 g, 1.60 mmol) according to the general procedure of Example 2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>CO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Solvent: CO
Product: CN1CCC(N2CCc3ccc(N)cc32)CC1
Reaction time: 8 h

Procedure:
1-(1-Methyl(4-piperidyl))-6-nitroindoline (3 g, Step A) was dissolved in 100 mL MeOH, and the mixture was bubbled with N2 for 10 min. 10% Pd/C (200 mg) was added and the mixture was stirred under H2 overnight. The mixture was filtered through Celite® and concentrated in vacuo to afford a light yellow oil. MS: 232 (M+1). Calc'd. for C14H21N3—231.34.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)/[C:18](=[CH:22]\[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)/[C:17]([CH3:31])=[C:16]2[CH2:32][N:33]=[C:34]=[O:35]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)/[C:18](=[CH:22]\[C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)/[C:17]([CH3:31])=[C:16]2[CH2:32][NH:33][C:34]([N:3]([OH:4])[CH3:2])=[O:35]
Reactant: CNO
Reactant: CSc1ccc(/C=C2/C(C)=C(CN=C=O)c3cc(F)ccc32)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ccc(/C=C2/C(C)=C(CNC(=O)N(C)O)c3cc(F)ccc32)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of N-methyl hydroxylamine hydrochloride (9.82 g, 117.6 mmol) in THF (150 mL) at room temperature there was added triethylamine (16.3 mL, 117.6 mmol) and the mixture stirred for 10 minutes. There was added, over 15 minutes, a solution of the isocyanate from Step 1 in THF (100 mL). After 2 hours of stirring at room temperature, the THF was evaporated and the residue, on trituration with water, afforded a yellow solid which was filtered. This solid was stirred in ether (150 mL) and filtered again. This crude material was chromatographed on silica gel eluting with 5% ethanol in methylene chloride. The more polar component of the mixture was stirred with methylene chloride (50 mL) for 2 hours and filtered and the solid crystallized from ethyl acetate to afford the pure title product as yellow crystals, mp 190-192° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
To 3-bromophenylacetic acid (5.027 g, 23.4 mmol) in MeOH (50 mL) was added thionyl chloride (3.4 mL, 46.8 mmol), and the reaction was stirred at 65° C. for 5 hours. Once no starting material was seen by analytical LCMS, the mixture was concentrated and the residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. 1N Aqueous NaOH was added to adjust the pH to basic, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound.