Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH2:17][Cl:18]>C(#N)C>[Cl:18][CH2:17][CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: ClCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: ClCCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of 4-iodophenol (1.0 g) in acetonitrile (10 mL), cesium carbonate (3.0 g) and 1-bromo-2-chloroethane (0.8 g) were added and the mixture was heated to 100° C., at which it was stirred for 4 hours. Additional 1-bromo-2-chloroethane (1.0 g) was further added and stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=11:1) to give the titled compound (0.87 g, 68%) as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.C(O)(C)(C)C.[CH2:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1)[CH2:14][CH3:15].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])=[O:29]>C1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28](=[O:29])[CH2:27][CH2:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:13][CH2:14][CH3:15])=[CH:22][CH:21]=1)=[O:25]
Reactant: CCCOc1ccc(C(C)=O)cc1
Reactant: O=C(CBr)c1ccccc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: CCCOc1ccc(C(=O)CCC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 37.4 %

Procedure:
To a solution of 11.7 gm (85.6 mmol) of fused ZnCl2 in 20 mL of benzene was 10 added 8.50 mL (64 mmol) of triethylamine and 6.12 mL (64 mmol) of dry t-butanol. After dissolution at room temperature 11.45 gm (64 mmol) of 1-(4-propoxyphenyl) ethanone 100 and 10.0 gm (42.8 mmol) of 2-bromo-1-(2-chlorophenyl) ethanone 99. The mixture was allowed to stir at room temperature for 6 days. The solvents were removed at reduced pressure and the residue added to 100 mL of water. The aqueous phase was extracted with ethyl acetate (200 mL) twice. The combined organic layers were washed with water (150 mL), saturated brine, dried (Na2SO4) and the solvents removed at reduced pressure. Column chromatography of the residue using 2%-4%-8% ethyl acetate-hexanes yielded 5.3 gm (37%) of a light yellow solid. This was recrystallized from hot hexanes-ethyl acetate. 1H NMR (400 MHz, CDCl3) δ: 1.04 (t, 3H, J=7.42 Hz), 1.82 (m, 2H), 3.36 (m, 2H), 3.42 (m, 2H), 3.98 (t, 2H, J=6.5 Hz), 6.92 (d, 2H J=8.9 Hz), 7.38 (m, 3H), 7.64 (m, 1H), 7.97 (m, 2H).
Reaction SMILES: NC1N=C2C(O)=CC=CN2N=1.[NH2:12][C:13]1[N:31]=[C:16]2[C:17]([O:21][CH2:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[C:25]#[N:26])=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1.Br[C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[NH2:12][C:13]1[N:31]=[C:16]2[C:17]([O:21][CH2:22][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[C:25]#[N:26])=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1.[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([C:36]2[CH:35]=[CH:34][C:33]([NH:12][C:13]3[N:31]=[C:16]4[C:17]([O:21][CH2:22][C:23]5[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=5[C:25]#[N:26])=[CH:18][CH:19]=[CH:20][N:15]4[N:14]=3)=[CH:38][CH:37]=2)[CH2:40][CH2:41]1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: N#Cc1ccccc1COc1cccn2nc(N)nc12
Agent: Nc1nc2c(O)cccn2n1
Product: CN1CCN(c2ccc(Nc3nc4c(OCc5ccccc5C#N)cccn4n3)cc2)CC1

Procedure:
262 a) 2-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl)-benzonitrile was prepared from 2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-ol (0.200 g, 1.33 mmol) 2-bromomethyl-benzonitrile (0.274 mL, 1.40 mmol) in a manner analogous to Example 260c. Product was isolated as a white solid. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.21 (d, J=6.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.78-7.76 (m, 2H), 7.62-7.58 (m, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.81-6.78 (m, 1H), 5.94 (s, 2H), 5.44 (s, 2H). MS=266 (MH)+. 262 b) 2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl}benzonitrile was prepared from 2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yloxymethyl)-benzonitrile (115.0 mg, 0.434 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (128 mg, 0.500 mmol) in a manner analogous to Example 2d. Product was isolated as a pale orange solid (0.101 g, 53%). MP=156-157° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.32 (s, 1H), 8.40 (d, J=6.5 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.80 (d, J=4.5 Hz, 2H), 7.62-7.60 (m, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 6.98-6.88 (m, 3H), 5.49 (s, 2H), 3.04-3.02 (m, 4H), 2.47-2.44 (m, 4H), 2.22 (s, 3H). MS=440 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:38]([N:45]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[S:46]([CH2:49][CH2:50][CH2:51]Cl)(=[O:48])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:51][CH2:50][CH2:49][S:46](=[O:48])(=[O:47])[N:45]([CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: O=S(=O)(CCCCl)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCS(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)c2ccccc21
Reaction time: 8 h

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (300 mg, 0.693 mmol) was dissolved in DMF (10 mL) at room temperature. Cs2CO3 (1.12 g, 3.46 mmol) was added followed by 3-chloro-propane-1-sulfonic acid dibenzylamide (350 mg, 1.03 mmol) and the reaction was allowed to stir overnight. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (2/1 hexanes/ethyl acetate) to afford the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39](I)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][CH2:32][C:33]2[NH:42][C:36]3=[N:37][CH:38]=[C:39]([C:2]4[CH:7]=[CH:6][C:5]([S:8]([N:11]5[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]5)(=[O:10])=[O:9])=[CH:4][CH:3]=4)[CH:40]=[C:35]3[N:34]=2)[CH:26]=1
Reactant: CC1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC(C)CC5)cc4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 41.8 %

Procedure:
A mixture of 0.477 g of 1-(4-bromo-benzene-sulfonyl)-4-methyl-piperidine, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2 for 6 hours. To the resulting mixture 5 ml of degassed dioxane, 0.342 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.104 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.25 g of potassium carbonate and 0.076 g of lithium chloride in 3 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 110° under N2 for 17 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated. Crystallization of the residue from ethylacetate and recrystallization from acetonitril gives 0.185 g of the title compound as a solid of m.p. 186-188° C. The mass spectrum shows the molecular peak MH+ at 492.4 Da.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[C:20]#[N:21]>CN(C)C=O.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=2[C:20]#[N:21])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Cl
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(OCc2cccc([N+](=O)[O-])c2C#N)ccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 57.7 %

Procedure:
4-Chloro-3-methylphenol (0.12 g, 0.83 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.2 g, 0.83 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried to yield 145 mg of 2-(4-chloro-3-methylphenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11](N)=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[CH:29][C:30]([N+:40]([O-])=O)=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:32]=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:10]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:31]2[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=2[N:40]=1)[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
(Prep 2) To a suspension of (S)-Boc-alaninamide (79.4 g, 0.42 mol) in DCM (750 mL) was added triethyloxonium tetrafluoroborate (69.5 g, 0.37 mol) and the reaction mixture stirred at RT for 2 h, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (750 mL). (5-Fluoro-2-nitrophenyl)pyridin-2-yl-amine (57.1 g, 0.28 mol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white foam (60.3 mg, 60%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)=[O:4].[OH-].[Na+].O.Cl>CO>[C:10]([N:7]1[CH:8]=[N:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
A mixture of 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (500 mg, 1.35 mmol) in methanol at 25° C. was treated with a 1N aqueous sodium hydroxide solution (4.0 mL). The reaction was stirred at 25° C. for 24 h. At this time, the reaction mixture was poured into water (100 mL) and acidified with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (2×150 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×150 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid (326 mg, 67%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.37 (s, 1H), 7.39 (m, 9H), 7.05 (m, 6H), 3.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:22]([C:21]2[CH:20]=[N:19][N:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@@H:8]4[C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:25][CH3:26])=[N:14][C:15]=23)=[O:23])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC3CC3)c2n1
Yield: 68 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and cyclopropylamine to yield the title compound as a white solid (19 mg, 68% yield). MS (apci) m/z=396.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:40][C:41]([F:56])([S:52](F)(=[O:54])=[O:53])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][S:52]([C:41]([F:40])([F:56])[C:42]([F:50])([F:51])[C:43]([F:48])([F:49])[C:44]([F:47])([F:46])[F:45])(=[O:54])=[O:53])[CH:17]=[CH:16][C:15]=2[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC1(C)CC(c2ccc(O)cc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C)CC(c2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
A mixture of 4-[5-hydroxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (1.5 g, 3.60 mmol) produced in Example (81b), 4-dimethylaminopyridine (22.2 mg, 0.18 mmol), diisopropylethylamine (0.758 mL, 4.32 mmol) and dichloromethane (10 mL) was cooled in an ice water bath and stirred under a nitrogen atmosphere. Perfluorobutanesulfonyl fluoride (0.773 mL, 3.96 mmol) was then added dropwise thereto. After stirring for 1 hour and 20 minutes under the same conditions, stirring was continued for 16 hours at room temperature. Water was added to the reaction mixture and extraction was performed with dichloromethane. The separated organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 2.41 g of the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:31]=[CH:32][CH:33]=2)O1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH:29]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCOCC5)c4)nc23)CCCCC1

Procedure:
(1-Methyl-cyclohexyl)-[2-(3-morpholin-4-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine following general procedures as described in these Examples. MP 208-209° C., M+H=405.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH4+:20].[OH-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:20])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: [NH4+]
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 160.9 %

Procedure:
To a solution of 4-methyl-2-nitrobenzoic acid (1.0 g, 5.52 mmol) in toluene (5 mL) was added oxalyl chloride (1.04 g, 8.28 mmol) at 0° C. and the reaction mixture was stirred at rt for 2 h. Then the reaction mixture was concentrated and the concentrate was dissolved in THF (5 mL). Then NH4OH (1.93 g, 55.20 mmol) was added to the solution at 0-5° C. and the reaction mixture was stirred at rt for 4 h before it was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated to afford 1.6 g of the desired product. 1H NMR (300 MHz, DMSO-d6): δ 8.08 (br s, 1H), 7.79 (s, 1H), 7.62 (br s, 1H), 7.57-7.50 (m, 2H), 2.41 (s, 3H).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]1([C:27]2[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:27]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:28]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: COC(=O)C(Oc1cccc(-c2ccccc2)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
In a similar manner as in Example 39, 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate is reacted with 4.25 g of 3-phenylphenol in methanol to give a yellow oil, which is subjected to fractional bulb-to-bulb distillation (175°-178° C at 0.02 mm) to remove volatile impurities. The glassy residue is subjected to filtration through 200 g of silica gel (benzene) and concentration to yield the product as an orange foam.
Reaction SMILES: C(OC([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[CH:16]=[C:11]2[C:10]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9]1)=O)(C)(C)C.[H][H]>[Pd].C(O)C>[N:17]1([C:15]2[CH:16]=[C:11]3[CH:10]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:9][NH:8][C:12]3=[CH:13][N:14]=2)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: CCOC(=O)C=Cc1cn(C(=O)OC(C)(C)C)c2cnc(-n3cncn3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CNc2cnc(-n3cncn3)cc21

Procedure:
Ethyl 3-[1-tert-butyloxycarbonyl-5-(1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-3-yl]prop-2-enoate (0.29 g) was hydrogenated over palladium on carbon (10%, 0.435 g) in ethanol (50 mL) at 50 psi of hydrogen for 75 min. The catalyst was removed by filtration and the solvent evaporated in vacuo to give the title compound. (0.24 g) as a colourless solid. This was used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl>C(OCC)(=O)C.[Pd]>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH3:4])=[C:2]([OH:1])[CH:9]=1
Reactant: COc1ccc(C=O)c(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C)c(O)c1
Reaction time: 8 h

Procedure:
A mixture of 2-hydroxy-4-methoxy-benzaldehyde (30.4 g, 0.20 mol), palladium/carbon (10%, 50% water, 30 g), concentrated HCl (15 ml) in 1500 ml of ethyl acetate was hydrogenated at 50 psi, at room temperature overnight, then filtered through Celite®. The filtrate was washed with water, brine, dried over sodium sulfate, concentrated, and purified using normal phase chromatography. 400 MHz 1H NMR (CDCl3) δ 7.01 (d, 1H), 6.44-6.38 (m, 2H), 4.65 (s, 1H), 3.79 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH2:6][CH:5]([S:8][C:9]2[CH:15]([CH3:16])[CH:14]3[N:11]([C:12](=[O:20])[CH:13]3[CH:17]([OH:19])[CH3:18])[C:10]=2[C:21]([OH:23])=[O:22])[CH2:4]1.[Cl:24][CH2:25][CH:26]1[C:30](=O)[O:29]C(=O)[NH:27]1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[NH2:27][CH:26]([CH2:25][Cl:24])[C:30]([NH:1][CH2:2][CH:3]1[O:7][CH2:6][CH:5]([S:8][C:9]2[CH:15]([CH3:16])[CH:14]3[N:11]([C:12](=[O:20])[CH:13]3[CH:17]([OH:19])[CH3:18])[C:10]=2[C:21]([OH:23])=[O:22])[CH2:4]1)=[O:29]
Reactant: O=C1NC(CCl)C(=O)O1
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CNC(=O)C(N)CCl)C3)C(C)C12
Yield: 38.7 %

Procedure:
The title compound is prepared by the procedure of Example 47 using 0.0685 g of product from Example 46 in 1.5 ml of sodium phosphate buffer (pH 8.5) and 0.0299 g of product from Example 53 to give 0.0347 g of the desired product.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].Cl[C:14](=[CH2:17])[C:15]#[N:16]>C(O)C>[C:2]([N:6]1[C:15]([NH2:16])=[CH:14][CH:17]=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: C=C(Cl)C#N
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1nccc1N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To 600 ml of ethanol were successively added 59.94 g of tert-butylhydrazine hydrochloride, 79.3 g of sodium acetate and 50 ml of 2-chloroacrylonitrile at room temperature, followed by stirring the reaction mixture at 80° C. for 12 hours. After removing the solvent in vacuo, water was added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1-1/2) to give the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([O:12][N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([S:9]([O:12][N:13]1[C:14](=[O:19])[CH2:15][CH2:16][C:17]1=[O:18])(=[O:10])=[O:11])[CH2:23][CH2:22][O:21][CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)ON1C(=O)CCC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCN(C(=O)OC(C)(C)C)S(=O)(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of N-(t-butoxycarbonylaminosulfonyloxy)-succinimide (272 mg), 2-methoxyethanol (84.4 mg) and triphenylphosphine (291 mg) in tetrahydrofuran (5 ml) was added diethyl azodicarboxylate (193 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (2:1, 1:1) to give N-(N-t-butoxycarbonyl-N-(2-methoxyethyl)aminosulfonyloxy)succinimide as colorless oil (205 mg).