Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([CH2:31][N+:32]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].O>COCCOC>[CH2:15]([CH:9]1[CH2:10][CH:11]([C:31]#[N:32])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1Cc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C#N)CC1Cc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 2-benzyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (15 g, 51.8 mmol) (from SYNTECH) in DME (250 mL) under nitrogen atmosphere was simultaneously added toluene-4-sulfonylmethyl isocyanide (15.2 g, 77.7 mmol, in 250 mL DME) and potassium tert-butoxide (156 mL, 1 M in tert-butanol) over 1 h so that the temperature was kept below −10° C. The solution was stirred at −10° C. for 2 h and then allowed to reach room temperature over 16 h. To the reaction mixture was added H2O (400 mL) and the solution was stirred for 20 min and then extracted with DEE (×3) and EtOAc (×3). The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by column chromatography using EtOAc/heptane (10-60% gradient EtOAc) to yield tert-butyl 2-benzyl-4-cyanopiperidine-1-carboxylate (11.85 g, 76%). 1H NMR (600 MHz, cdcl3) δ 1.38-1.46 (m, 9H), 1.63-2.14 (m, 4H), 2.62-3.33 (m, 4H), 4.17 (m, 1H), 4.48 (m, 1H), 7.11-7.41 (m, 5H); MS m/z 301 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2)([O-])=O>CCOC(C)=O.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a suspension of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.77 g, 7.16 mmol) in EtOAc (100 μL) and MeOH (100 mL) was added 10% Pd/C (400 mg) and the reaction stirred vigorously under hydrogen (ca. 1 atm). After 1 h, the catalyst was filtered off and the filtrate was concentrated to yield 1.50 g (97%) of the title compound as a pale brown solid. MS: m/z=218 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:14]([CH3:17])([CH3:16])[CH3:15])(=O)C.[OH-].[Na+]>CO.O>[C:14]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[OH:4])[C:9]([OH:11])=[O:10])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)O)ccc1O
Yield: 98.8 %

Procedure:
50.0 g of 4-acetoxy-3-tert-butylbenzoic acid are dissolved in 200 g of methanol. A solution of 10.2 g of sodium hydroxide in 180 ml of water is added. The mixture is refluxed for 3 hours. The methanol is removed, and the mixture is acidified with hydrochloric acid (10%) at 10° C. The precipitate is filtered off and washed, giving 40.6 g of product in the form of colourless crystals having a melting point of from 158° to 159° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[N:23])[CH:17]=[CH:16][C:15]=1[S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>C(O)C>[C:22]([CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1)#[N:23]
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCC#N)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCC#N)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 7d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 38c (53 mg, 0.17 mmol) for 18 h following the procedure from Example 7g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (9 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.03 (s, 3 H) 2.76 (s, 3 H), 5.23 (s, 2 H), 6.32 (d, J=6.99 Hz, 1 H), 7.18 (d, J=8.46 Hz, 2 H) 7.23 (dd, J=8.82, 2.57 Hz, 1 H), 7.31 (d, J=2.57 Hz, 1 H), 7.38 (d, J=8.82 Hz, 1 H) 7.45 (d, J=8.82 Hz, 2 H), 7.80 (d, J=8.46 Hz, 1 H), 8.41 (d, J=6.99 Hz, 1 H) 8.96 (d, J=8.46 Hz, 1 H), 10.01 (s, 1 H), 11.04 (s, 1 H), 14.42 (s, 1 H); MS (ESI+) m/z 456 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[H-].[Na+].Cl[C:10]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[NH:33][C:32]4=[O:40])[CH2:27][CH2:26]3)=[CH:20][CH:19]=2)[C:15]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:14][C:11]=1[C:12]#[N:13]>CS(C)=O.O>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][O:6][C:10]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[NH:33][C:32]4=[O:40])[CH2:29][CH2:30]3)=[CH:20][CH:19]=2)[C:15]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCOc1nc(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)c(-c2ccccc2)cc1C#N
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a mixture of N,N dimethylaminoethanol in DMSO (1 mL) was added NaH (60% dispersion in mineral oil, 0.019 g, 0.481 mmol). The mixture was heated to 50° C. for 15 min. After cooling, 2-Chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (2-6, 0.050 g, 0.096 mmol) was added and the reaction was allowed to stir for 16 hr at rt. The resulting mixture was diluted with water (10 mL) and the resulting precipitate was filtered. The filtered cake was purified by reverse phase HPLC. (5% CH3CN: 95% H2O+0.01% TFA to 95% CH3CN: 5% H2O+0.01% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 10.93 (s, 1H), 9.86 (bs, 2H), 8.45 (s, 1H), 7.40-7.55 (m, 4H), 7.25-7.40 (m, 6H), 7.00 (d, J=2.93, 3H), 4.85 (t, J=4.89, 2H), 4.45 -4.55 (m, 1H), 4.34 (s, 2H), 3.64 (bs, 2H), 3.46 (d, J=11.72, 2H), 3.10-3.25 (m, 2H), 2.94 (d, J=4.15, 6H), 2.56-2.69 (m, 2H), 1.93, (d, J=12.00, 2H). HRMS m/z (M+H) Calcd: 573.2973, found: 573.2957.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH:7]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:19]=[CH:18][C:16]([N:17]=[C:1]=[O:2])=[CH:15][CH:14]=2)[N:9]=[CH:10][N:11]=1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=Nc1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: -20 °C

Procedure:
Apparatus: 2 litre 3-neck-roundbottle flask, dropping funnel, short Vigreux column and condenser. A phosgene solution (20% in toluene, 118 ml; 223 mmol) diluted with toluene (800 ml) under N2-atmosphere is cooled to approximately −20° C. Then a solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 18.52 g, 83.6 mmol) in CH2Cl2 (400 ml) is added dropwise. The resulting suspension is heated to distil off approximately 400 ml of solvent. Distillation Is continued (boiling point: 110° C.), while a mixture of phosgene solution (20% in toluene, 59 ml) and toluene (500 ml) is added dropwise, followed by toluene (250 ml). The resulting clear solution (a 250 ml) in the reaction vessel is cooled to rt, filtered and the filtrate concentrated in vacuo. Distillation of the resulting waxy crude product on the Kugelrohr apparatus (0.2 mbar, 200° C.) gives the title compound as a solid: m.p.: 103° C.; MS: [M+1]+=302; 1H-NMR (CDCl3): 8.57 (s, 1H), 7.17 (d, 2H), 7.10 (d, 2H), 6.95 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.C(=O)([O-])[O-:12].[Na+].[Na+].C(OO)(=O)C>>[CH3:9][C:8]([CH:5]1[CH2:6][CH:7]2[O:12][C:2]2([CH3:1])[CH2:3][CH2:4]1)=[CH2:10]
Reactant: O=C([O-])[O-]
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Agent: CC(=O)OO
Agent: [Na+]
Product: C=C(C)C1CCC2(C)OC2C1
Reaction time: 0.75 h

Procedure:
A mechanically stirred mixture of 1 kg. (7.3 mol.) of d-limonene (7.3 mol.) and sodium carbonate (310.6 g) was cooled to 0°-10° C., and treated with 1.61 kg. (9.1 mol.) 40% peracetic acid by dropwise addition. After the addition was complete, the reaction mixture was stirred for another 45 min., washed with ice water, sodium carbonate, and brine. The oil was dried over magnesium sulfate, and distilled to give recovered limonene (30 g), the cis-epoxide (257 g) and trans-epoxide (296 g), and diepoxide (82 g).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.C[Si](C)(C)[Cl:34]>CC(CC)=O>[ClH:34].[CH3:31][N:2]([CH3:1])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][CH2:5][CH:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:7][CH2:8]1.[CH3:31][N:2]([CH3:1])[C:3]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][CH2:5][CH:6]([NH:9][C:10]([NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(NC(=O)NCCc2c[nH]c3ccc(F)cc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
In order to produce the hydrochloride (compound 19), the more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexyl)-3-[2-(5-fluoro-1H-indol-3-yl)ethyl]urea (140 mg, 0.33 mmole) was dissolved in ethyl methyl ketone (3 ml) and combined with trimethylchlorosilane (60 μl, 0.45 mmole). The resulting solid was filtered out and dried. The hydrochloride of the more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexyl)-3-[2-(5-fluoro-1H-indol-3-yl)ethyl]urea was obtained in this manner as a colorless solid with a melting point of 197-199° C. in a yield of 152 mg (100%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[F:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH:2]=[N:13][C:12]1[CH:14]=[CH:15][C:9]([F:8])=[CH:10][C:11]=1[CH3:16])[CH3:7]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Nc1ccc(F)cc1C

Procedure:
A solution of ethyl glyoxalate (50% solution in toluene—40.8 mL) in toluene (180 mL) was heated to reflux for 1.5 hours under a Nitrogen atmosphere, in a flask equipped with a Dean Stark apparatus. Then, a solution of 4-fluoro-2-methyl-aniline (10 g) in dry toluene (20 mL) was slowly added. The mixture was heated to reflux for 3 hours, then it was concentrated in vacuo. The residue was purified by flash chromatography (toluene/CH/AcOEt 4:4:2) to give the title compound (13.06 g) as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, methyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (24a) (0.62 g, 1.6 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.24 g (3.2 mmol) of sodium azide (NaN3). After work-up, the crude material (24b) was used in the next step without further purification. MS (ESI) m/z 421.96 (M+Na)+.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[C:9]1([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>O1CCCC1>[C:3]([CH:22]([C:19]1[CH:20]=[CH:21][C:16]([S:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][CH:18]=1)[C:23]#[N:24])(=[O:5])[CH3:4]
Reactant: CCOC(C)=O
Reactant: N#CCc1ccc(Sc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)C(C#N)c1ccc(Sc2ccccc2)cc1
Yield: 73.3 %

Procedure:
To a stirred suspension of 144 mg of 60% sodium hydride, in 10 ml of tetrahydrofuran at 0° C. under nitrogen atmosphere was added a mixture of 396 mg of ethyl acetate, 675 mg of 4-phenylthiophenylacetonitrile and 5 ml of tetrahydrofuran. Thirty minutes later, the ice bath was removed. Seventeen hours later, the tetrahydrofuran was distilled off in vacuo, and 10 ml of 2N hydrochloric acid and 20 ml of dichloromethane were added and separated, and the water layer was further extracted twice in 20 ml of dichloromethane. The organic layer and extract were combined, and dried by anhydrous magnesium sulfate, and concentrated in vacuo, and the residue was isolated and refined by silica gel chromatography (the eluent was a mixed solvent of hexane:ethyl acetate at a (v/v) rate of 4:1), and 587 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:28])[C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[O:4])=[O:3].C[C:30]([CH3:33])([O-:32])[CH3:31].[K+]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:24][C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=[CH:19][C:14]=1[O:13][C:11]1[CH:10]=[CH:9][C:8]([N+:25]([O-:27])=[O:26])=[C:7]([CH:12]=1)[C:6]([N:5]([C:6](=[O:28])[C:7]1[CH:33]=[C:30]([O:32][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[Cl:24])[CH:31]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])[S:2]([CH3:1])(=[O:4])=[O:3])=[O:28]
Reactant: CC(C)(C)[O-]
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N(C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To N-methylsulfonyl-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitro-benzamide (20.0 grams, 45.6 millimoles) dissolved in 100 ml tetrahydrofuran was added potassium tertiary butoxide in tetrahydrofuran with cooling. A solution of the acid chloride product as described in Example 1 in tetrahydrofuran was then added and the mixture stirred at ambient temperature for forty eight hours under nitrogen with precautions taken to exclude moisture throughout this procedure. The mixture was then diluted with toluene, washed three times with water and saturated sodium chloride solution. The organic phase was concentrated by vacuum to dryness. The residue was shaken with toluene then reconcentrated three times. The final residue was covered with toluene, shaken, the insolubles filtered off, and washed several more times with toluene and hexane. The material was triturated for 30 minutes by stirring with 50 ml hexane. The insolubles were filtered off and dried. The material was purified further by trituration with 5% potassium carbonate followed by drying and recrystallization from toluene/hexane mixtures. The desired product had a melting point of 165.5°-167.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
70 (172 mg, 0.81 mmol), methyl 4-(bromomethyl)benzoate (205 mg, 0.89 mmol), and K2CO3 (225 mg, 1.63 mmol) were suspended in DMF (3.00 mL), and stirred overnight at room temperature. The reaction mixture was purified directly via flash chromatography on silica gel to provide 454 (34 mg, 11% yield) as a white powder. LC-MS (M+H=360, obsd.=360). 1H NMR (400 MHz, DMSO-D6) δ 11.49 (s, 1H), 8.51 (m, 1H), 8.41 (d, J=3.0, 1H), 7.97 (dd, J=8.6, 19.3, 2H), 7.58 (d, J=8.2, 2H), 7.38 (m, 1H), 7.37 (s, 1H), 7.24 (dd, J=4.7, 7.9, 1H), 6.95 (d, J=11.0, 1H), 4.62 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[C:14]1([NH:24][CH2:25][CH2:26][NH2:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:24][CH2:25][CH2:26][NH:27][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCCNc1cccc2ccccc12
Product: O=C(NCCNc1cccc2ccccc12)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(naphthalen-1-ylamino)ethylamine. The product was purified by mass directed purification to give the title compound as a brown solid. δH (CD3OD): 3.55 (2H, t), 3.80 (2H, t), 6.68 (1H, d), 7.04 (1H, s), 7.14 (1H, d), 7.28 (1H, t), 7.36-7.42 (2H, m), 7.65 (1H, s), 7.70-7.74 (1H, m), 7.98-8.02 (1H, m), 8.58 (1H, s); m/z (ES+)=365 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[P:10]([O:15]C)([O:13][CH3:14])[O:11][CH3:12]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:11][P:10]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])(=[O:15])[O:13][CH3:14]
Reactant: Cc1ccc(I)c(C)c1
Reactant: COP(OC)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COP(=O)(OC)c1ccc(C)cc1C
Temperature: 25 °C
Yield: 95 %

Procedure:
4-Iodo-m-xylene (8.62 mmol), trimethyl phosphite (12.07 mmol) and palladium acetate (0.86 mmol) were mixed together in acetonitrile (12 ml), in a microwave tube. The vessel was sealed and placed in a microwave to react at 160° C., for 45 minutes. After cooling to room temperature, acetonitrile was removed. The crude material was purified by silica gel chromatography to yield Intermediate I.4 as an oil (95%). Intermediate 1.4 was characterized by the following spectroscopic data: 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.35 (s, 3H), 2.51 (s, 3H), 3.74 (d, J=12.0 Hz, 6H), 7.08-7.09 (m, 2H), 7.75-7.81 (m, 1H); 31P NMR (CDCl3, 162 MHz) δ (ppm) 23.18 (s, 1P); and MS (ESI, EI+) m/z=215 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:13]([CH3:15])[CH3:14])[C:6]2=[O:12].[N:16]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:11].[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][NH2:16])=[C:3]2[C:7]=1[C:6](=[O:12])[N:5]([CH:13]([CH3:15])[CH3:14])[CH2:4]2
Reactant: CC(C)N1Cc2c(N)ccc(Cl)c2C1=O
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)N1Cc2c(NN)ccc(Cl)c2C1=O
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 4.0 grams (0.018 mole) of 4-amino-7-chloro-2-(1-methylethyl)isoindolin-1-one in 40 mL of concentrated hydrochloric acid was cooled in an ice-water bath, and a solution of 1.2 grams (0.018 mole) of sodium nitrite in 20 mL of water was added dropwise while maintaining the reaction mixture temperature under 5° C. Upon completion of addition, the reaction mixture was stirred for about 45 minutes, then a solution of 8.8 grams (0.039 mole) of tin(II) chloride in 20 mL of concentrated hydrochloric acid was added dropwise while still maintaining the reaction mixture temperature under 5° C. After this time the reaction mixture was stirred for about one hour at 5° C., then it was filtered to collect, after drying, 4.6 grams of subject compound, mp 186° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1](NN)(=O)C.[Br:6][C:7]1[C:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:9][C:10]2[N:11]([C:13]([CH2:16][C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[N:14][N:15]=2)[CH:12]=1>C(O)(=O)C.FC(C1C=CC=CC=1)(F)F>[Br:6][C:7]1[C:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:9][C:10]2[N:11]([C:13]([CH2:16][C:17]3[C:18]([CH3:1])=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)=[N:14][N:15]=2)[CH:12]=1
Reactant: CC(=O)NN
Reactant: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Solvent: FC(F)(F)c1ccccc1
Solvent: CC(=O)O
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Yield: 60 %

Procedure:
The title compound (61 mg, 60%) as a white powder was prepared from N′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-trifluoromethyl)pyridin-3-yl)acetohydrazide (100 mg, 0.20 mmol) in glacial acetic acid (0.6 mL) and (trifluoromethyl)benzene (1.8 mL) by the procedures analogous to those described for 6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56D). LC/MS (method B): retention time 1.83 min, [M+H]+=481.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([NH2:8])[CH:7]=1.[CH2:10]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>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.[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH3:19])=[C:6]([NH2:8])[CH:7]=1
Reactant: C#CCCN1CCC[C@H]1C
Reactant: Nc1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CCCN1CCC#Cc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of Example 168B (0.2 g, 0.67 mmol), 1-but-3-ynyl-(2R)-2-methyl-pyrrolidine (7.4 mL as a 0.1 M solution in acetonitrile, 0.74 mmol), and triethylamine (10 mL, 72.0 mmol) was degassed with nitrogen for 10 minutes while stirring at r.t. Next, Pd(PPh3)2Cl2 (0.010 g, 0.013 mmol) and CuI (0.003 g, 0.013 mmol) were added and the resulting mixture was degassed for an additional 10 minutes, sealed, and stirred at r.t. for 18 hours. Contents were then concentrated under reduced pressure and the residue was dissolved in 100 mL dichloromethane, washed twice with each: 50 mL sat. NaHCO3, 50 mL water, and 50 mL brine, dried with Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to afford the product in 30% yield as a light yellow oil. 1H NMR (CD3OD, 300 MHz) δ 7.03 (d, J=9 Hz, 1H), 6.88 (d, J=3 Hz, 1H), 6.68 (dd, J=3, 9 Hz, 1H), 3.41-3.20 (m, 2H), 2.79-2.52 (m, 5H), 2.12-2.04 (m, 1H), 1.92-1.82 (m, 2H), 1.56-1.47 (m, 1H), 1.25 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 308.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[Cl:9].N[C:13]([CH3:17])=[CH:14][C:15]#[N:16]>>[NH2:16][C:15]1[N:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[N:11]=[C:13]([CH3:17])[CH:14]=1
Reactant: CC(N)=CC#N
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: Cc1cc(N)n(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
3,4-Dichlorophenyl hydrazine HCl (50.0 g.) was reacted with 3-amino-2-butene nitrile (18.31 g.) as described in Example XLIII to give 18.7 g. product, mp 110°-112°.