Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:23]([OH:38])([C@H:30]([S:32][CH:33]([CH2:36]O)[CH2:34][OH:35])[CH3:31])[CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:11]([C:10]1[CH:13]=[CH:14][C:7](/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[C@H:2]2[O:35][CH2:34][C@H:33]([S:32][C@H:30]([CH3:31])[C@:23]([C:17]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=3[F:15])([OH:38])[CH2:24][N:25]3[CH:29]=[N:28][CH:27]=[N:26]3)[CH2:36][O:1]2)=[CH:8][CH:9]=1)#[N:12]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: N#Cc1ccc(/C=C/C=C/C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of 240 mg (1.31 mmol) of 4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile [prepared as described in Step 1(i) above], 392 mg (1.09 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]-thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350)], 249 mg (1.31 mmol) of p-toluenesulfonic acid monohydrate, 16 ml of dichloromethane and 3.9 g of molecular sieves 4A was stirred at ambient temperature over night. Aqueous sodium hydrogen carbonate was then added to the reaction mixture and insoluble material was removed by filtration. The resulting filtrate was extracted with ethyl acetate and the organic layer was dried and then concentrated. The resulting residue was purified by chromatography on silica gel (15 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 465 mg (yield 81%) of the title compound as a solid. This solid was recrystallized from a mixture of ethyl acetate and hexane to afford crystals.
Reaction SMILES: C(Cl)Cl.[CH:4]12[CH2:9][CH:8]1[CH2:7][N:6]([C:10]1[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[C:13]([C:27]([OH:29])=O)=[CH:12][N:11]=1)[CH2:5]2.[OH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:4]12[CH2:9][CH:8]1[CH2:7][N:6]([C:10]1[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[C:13]([C:27]([NH:37][C@H:34]3[CH2:35][CH2:36][C@H:31]([OH:30])[CH2:32][CH2:33]3)=[O:29])=[CH:12][N:11]=1)[CH2:5]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1F
Reaction time: 17 h

Procedure:
In the mixture of DCM (20 mL) and THF (20 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (580 mg, 1.62 mmol), trans-4-hydroxycyclohexylamine (187 mg, 1.62 mmol), TEA (485 mg, 4.79 mmol) and HATU (2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (743 mg, 1.95 mmol). The reaction was conducted at ambient temperature for 17 h. The solvent was removed by evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and concentrated to give a solid, which was purified by silica gel column chromatography (DCM/methanol=50/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-formamide as a faint yellow solid (200 mg, 27.1% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=1[O-:18].C(=O)(O)[O-].[Na+]>>[Br:10][C:11]1[CH:16]=[C:15]([N+:1]([O-:4])=[O:2])[CH:14]=[C:13]([CH3:17])[N+:12]=1[O-:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(Br)[n+]1[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Temperature: 70 °C
Yield: 40 %

Procedure:
Concentrated nitric acid (4 mL) was added to cold concentrated sulfuric acid (7 mL). 2-Bromo-6-methyl-pyridine 1-oxide (820 mg, 4.36 mmol) was added to this and then heated at 70° C. for 4 h. The mixture was cooled and poured slowly into ice-cold water (100 mL) and basified to pH ˜8 with sodium bicarbonate solution. This was extracted with ethyl acetate (4×50 mL) then the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by washing with pentane (50 mL) to afford 2-bromo-6-methyl-4-nitro-pyridine 1-oxide (0.41 g, 40%) as a free flowing yellow solid.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:25]1([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:37][C:34]1[CH:35]=[CH:36][C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1ccc(C2CCCCC2)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 82.1 %

Procedure:
As described in Example 44, 8.72 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate is reacted with 4.05 g of p-cyclohexylphenol to give 8.81 g of product as off-white crystals. Recrystallization from methanol gives white crystals, mp 93°-95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][N+:13]([CH3:16])=[CH:14]Cl.[Cl-]>>[CH3:12][N:13]([CH3:16])[CH:14]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]=[O:11]
Reactant: C[N+](C)=CCl
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: [Cl-]
Product: CN(C)C=C(C=O)c1ccc(F)cc1

Procedure:
In a manner similar to Example 1, p-fluorophenyl acetic acid is treated with Vilsmeier reagent to produce 3-(dimethylamino)-2-(4-fluorophenyl)-2-propenal. Treatment of this product with cyanoacetamide and sodium methoxide provides 1,2-dihydro-5-(4-fluorophenyl)-2-oxo-3-pyridinecarbonitrile. Hydrolysis of this product with acid gives 1,2-dihydro-5-(4-fluorophenyl)-2-oxo-3-pyridinecarboxylic acid. Treatment of this product with quinoline affords 5-(4-fluorophenyl)-2(1H)-pyridone, which is reacted with phosphorus oxychloride to give 2-chloro-5-(4-fluorophenyl)pyridine. Treatment of the above product with hydrazine produces 2-hydrazino-5-(4-fluorophenyl)pyridine. Treatment of this product with ethyl orthoacetate produces 6-(4-fluorophenyl)-3-methyl-1,2,4-triazolor[4,3-a]pyridine which yields the product of the Example on hydrogenation.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:28][C:27]3[CH2:26][CH2:25][NH:24][CH2:23][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[CH3:29][C:30]([CH3:32])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Br:1][C:2]1[C:3]([C:20]2[S:28][C:27]3[CH2:26][CH2:25][N:24]([CH:30]([CH3:32])[CH3:29])[CH2:23][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3c(s2)CCNC3)n1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCc2sc(-c3nc(NCCN4C(=O)NC(=O)C4(C)C)ncc3Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-(5-Bromo-4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (0.15 g, 032 mmol) was treated with acetone (1 mL), sodium triacetoxyborohydride (0.136 g, 0.64 mmol) in dicholoethane (5 mL). The reaction was stirred at room temperature overnight. The mixture was diluted with dichloromethane and water. The layers were separated and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The mixture was dried with sodium sulfate and purified by preparative HPLC. Yield=0.05 g. MS (M+H)+ 507/509.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][C:34]([OH:38])([C:36]#[CH:37])[CH3:35]>[Cu]I.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.C1COCC1>[CH3:25][O:24][C:19]1[C:18]([NH:17][C:13]2[N:14]=[CH:15][N:16]=[C:11]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([C:37]#[C:36][C:34]([CH3:35])([OH:38])[CH3:33])[CH:10]=4)[CH:6]=[N:7]3)[CH:12]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: C#CC(C)(C)O
Reactant: COc1ncccc1Nc1cc(-n2ncc3ccc(I)cc32)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ncccc1Nc1cc(-n2ncc3ccc(C#CC(C)(C)O)cc32)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pressure tube was added 6-(6-iodoindazol-1-yl)-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine (120 mg, 0.27 mmol) followed by triethylamine (2 mL) and THF (2 mL). Next, copper(I) iodide (5.15 mg, 0.027 mmol), bis(triphenylphosphine)palladium(II) chloride (18.96 mg, 0.027 mmol) and 2-methylbut-3-yn-2-ol (0.05 ml, 0.54 mmol) were added and the reaction vessel was sealed and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and DCM (5 ml) was added. The organics were washed with 0.5M HCl (2×3 ml), water (3 ml) and brine (3 ml), and dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Isolute column, 4:6 to 1:1 EtOAc:heptanes) to surrender the title compound as a white solid: 1H NMR (500 MHz, CDCl3) delta 1.69 (6H, s), 2.08 (1H, br. s.), 4.07 (3H, s), 6.99 (1H, dd, J=7.80, 4.97 Hz), 7.32-7.41 (2H, m), 7.69 (1H, d, J=8.20 Hz), 7.88 (1H, dd, J=4.97, 1.66 Hz), 8.19 (1H, s), 8.54-8.61 (1H, m), 8.77 (1H, s), 8.99 (1H, s); LC-MS: m/z=+401.10 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:24][CH2:25]1
Reactant: CC(C)CCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(CCC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:44]=[CH:43][S:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:44]=[CH:43][S:42][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1ccsc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccsc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 51.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 3-(chloromethyl)thiophene (0.27 g) as starting materials, 5-benzyloxy-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.48 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.39 g) was obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[CH:19][C:18]=3[O:30][CH3:31])=[O:16])[CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:41][C:42]([Cl:47])([Cl:46])[C:43](Cl)=[O:44]>ClCCl>[Cl:41][C:42]([Cl:47])([Cl:46])[C:43]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[CH:19][C:18]=3[O:30][CH3:31])=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:44]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2cccn2Cc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2ccccc2C)ccc1C(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanone of Step D (1.36 g, 3.33 mmol) in dichloromethane (15 mL) was added N,N-diisopropylethyl amine (1.2 mL, 6.89 mmol) followed by slow addition of trichloroacetyl chloride (1.1 mL, 9.85 mmol). The reaction mixture was stirred overnight at room temperature then was quenched with water. The organic phase was washed with 0.1 N hyrochloric acid followed by water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a green oil. Purification by flash chromatography on silica gel using a solvent system of 20% ethyl acetate in hexane gave 1.7 g of title product as a yellow foam.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[OH:14][C@H:15]([CH:19]([CH3:21])[CH3:20])[C:16](O)=[O:17].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[OH:14][C@H:15]([CH:19]([CH3:21])[CH3:20])[C:16]([NH:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])=[O:17]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 4-[(1S)-1-aminoethyl]-benzoic acid, methyl ester (5.8 g; 49.1 mmol), (2R)-2-hydroxy-3-methyl-butanoic acid (9.3 g; 51.9 mmol), 1-hydroxybenzotriazole (0.82 g; 6.1 mmol), and triethylamine (22 mL; 158 mmol) in CH2Cl2 (120 mL) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.2 g; 74.1 mmol). The cloudy mixture is stirred at room temperature overnight. The reaction mixture is washed with 1N HCl (2×150 mL) then brine. The organic layer is dried over MgSO4, filtered, concentrated, and dried under high vacuum to provide the title compound as a white solid (10.24 g, 75%). This material is used in the next step without further purification. MS (m/z): 280.0 (M+1).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[F:16][CH2:17][C:18]1[N:23]=[C:22]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:21]=[CH:20][CH:19]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][O:24][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][F:16])[N:23]=2)[CH2:28][CH2:29]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: FCc1cccc(OCCN2CCNCC2)n1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(CF)n2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(6-fluoromethyl-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[I:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(O)c(I)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C)nc1I
Temperature: 45 °C
Reaction time: 20 h

Procedure:
To 2-iodo-6-methyl-pyridin-3-ol (1.0 g, 4.25 mmol) and K2CO3 (1.18 g, 8.51 mmol) in acetone (20 mL) was added MeI (0.91 g, 6.38 mmol). The reaction was stirred at 45° C. under N2 for 20 h. The reaction was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography using dichloromethane to afford 1.04 g (98%) of I-95 as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=4[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1.[N:38]([O-])=O.[Na+]>CC(O)=O>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]5[N:26]=[N:38][NH:27][C:23]5=[CH:22][C:21]=4[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c(N)cc3-c3ccccc3)cc2)CC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc4nn[nH]c4cc3-c3ccccc3)cc2)CC1

Procedure:
6-(4-{[4-(2-methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-2,3-diamine (4-4, 0.052 g, 0.106 mmol) was dissolved in 1 ml HOAc. NaNO2 (0.008 g, 0.117 mmol) was added. After 1 h the reaction was concentrated in vacuo and diluted with saturated aqueous NaHCO3. The mixture was extracted 3× with DCM. The combined extracts were dried over Na2SO4, filtered and concentrated to afford pure 5-(4-{[4-(2-methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-6-phenyl-1H-[1,2,3]triazolo[4,5-b]pyridine (5-1). 1H NMR (CDCl3) δ 8.42 (s, 1H), 7.73 (m, 1H), 7.59 (m, 1H), 7.38 (d, 2H, J=8.0 Hz), 7.31 (m, 4H), 7.22 (m, 4H), 4.19 (m, 1H), 3.64 (s, 2H), 3.10 (d, 2H, J=12.0 Hz), 2.67 (s, 3H), 2.59 (m, 2H), 2.20 (t, 2H, J=11.6 Hz), 1.86 (d, 2H, J=10.0 Hz). MS m/z (M+H)=500.22.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)[O:19][CH:18]([CH2:20]OS(C)(=O)=O)[CH2:17][O:16]1.C(N(CC)CC)C>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:11][CH2:20][CH:18]([OH:19])[CH2:17][OH:16])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Solvent: CCN(CC)CC
Product: OCC(O)CNc1ccc(C2CCCCC2)cc1
Reaction time: 1 h
Yield: 19.8 %

Procedure:
8.05 g (44.6 mmol) of 4-cyclohexylaniline, 12.0 g (57 mmol) of methanesulfonic acid (RS)-2,2-dimethyl-1,3-dioxolan-4-yl-methyl ester and 11.2 ml (80 mmol) of triethylamine were held at 140° in a bomb tube for 4 h. The solvent was distilled off in a water-jet vacuum and the brown oily residue was treated with 50 ml of 3N hydrochloric acid and stirred at 50° for 1 hour. After cooling the mixture was extracted twice with 250 ml of ether each time, the aqueous phase was made alkaline with 3N sodium hydroxide solution and the product was taken up in ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and the solvent was distilled off. The oily residue crystallized upon treatment with ethyl acetate/hexane. 2.2 g of crystalline (RS)-3-(4-cyclohexyl-phenylamino)-propane-1,2-diol were obtained. M.p.: 121°-122° (dec.). A further 0.65 g of crystalline product was obtained from the mother liquor.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[CH:6]=[C:5]2[OH:16].[OH-].[Na+].O.O.O.C([O-])(=O)C.[Na+].[N+:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34])([O-:29])=[O:28]>O>[OH:16][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=3)[CH:3]=2)[CH:8]=[C:7]([S:12]([OH:15])(=[O:13])=[O:14])[CH:6]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc2cc(S(=O)(=O)O)cc(O)c2c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a suspension of 180 g of 6-amino-4-hydroxy-2-naphthalenesulfonic acid in 4 liters of water was added 75 ml of 10N sodium hydroxide. To the resulting solution was added 181.8 g of sodium acetate trihydrate, followed by 190 g of m-nitrobenzoyl chloride. The mixture was stirred vigorously under argon at room temperature for 8 hours and then filtered. The solid was washed with water, ethanol and then ether and dried at room temperature. The resulting brown solid (299.4 g) was added to a mixture of 1500 ml of water and 1200 ml of 1N sodium hydroxide and stirred under argon for one hour. The mixture was filtered and the filtrate was acidified to pH 3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, ethanol, then ether and dried in vacuo in hot water and gave 221.7 g of 4-hydroxy-6-m-nitrobenzamido-2-naphthalenesulfonic acid, sodium salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(NCc1ccccc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and benzyl isocyanate. m/z (ES+) 278 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])=[CH2:2].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7])=[CH2:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=Cc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=Cc1cccc(C(=O)Cl)c1

Procedure:
To a mixture of 3-vinylbenzoic acid (1.0 g, 6.75 mmol) in CH2Cl2 (20 mL) is added oxalyl chloride (2.35 mL, 3.42 g, 26.9 mmol) and 1 drop of DMF. After 2 h the solvent is removed under reduced pressure and the residue is redissolved in CH2Cl2 and concentrated again (4×) to afford the title compound which is used without further purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CCN(CC)CC.[CH3:17][O:18][C:19]([C:21]1[S:25][C:24]2[C:26]([NH2:30])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20]>C(Cl)Cl>[CH3:17][O:18][C:19]([C:21]1[S:25][C:24]2[C:26]([NH:30][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)=[O:20]
Reactant: O=C(O)c1cccnc1
Reactant: COC(=O)c1cc2cccc(N)c2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2cccc(NC(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
Nicotinic acid (401 mg, 3.26 mmol) was suspended in 20 mL CH2Cl2 and Et3N (330 mg, 3.26 mmol, 245 uL) was added to give a colorless solution. BopCl (829 mg, 3.26 mmol) was added and the reaction was stirred at room temperature for about 15 min, then a solution of 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (450 mg, 2.17 mmol) in 2 mL CH2Cl2 was added. The yellow solution was stirred at room temperature for 12 h. After this time, room temperature, the solvent was removed from the reaction and the residue was partitioned between EtOAc (100 mL) and water (75 mL). The layers were separated and the organic portion was washed with water (2×75 mL), brine (75 mL), dried (MgSO4), filtered and the solvent was removed in vacuo to afford 7-[(pyridine-3-carbonyl)-amino]-benzo[b]thiophene-2-carboxylic acid methyl ester as a yellow solid (460 mg, 45%).