Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Oc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3oc(Nc4ccc(Br)cc4)nc3c2)ccn1

Procedure:
The mixture containing 2-[(4-bromophenyl)amino]benzoxazol-5-ol (1 eq), potassium bis(trimethylsilyl)amide (4 eq), was stirred in dimethylformamide for 30 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methyl-carboxamide (1 eq) and Potassium carbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product. MS: MH+=439.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14](O)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][NH:18][CH3:19]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][N:18]([CH3:19])[CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CN(C)CC1(c2ccc(F)cc2)CCCCC1
Yield: 9 %

Procedure:
The title compound was synthesized from 1-(4-fluorophenyl)cyclohexane-carboxylic acid and dimethyl amine using General Procedure G, followed by General Procedure E in 9% yield as a solid. LCMS Rt=7.22 min, m/z=236 (M+1). 1H NMR (CDCl3, δ): 7.32 (dd, J=5.5, 8.9 Hz, 2H), 6.99 (t, J=8.8 Hz, 2H), 2.30 (s, 2H), 2.1 (m, 2H), 1.97, (s, 6H), 1.7-1.3 (m, 8H. 13C NMR (CDCl3, δ, mult): 162.0(0), 159.6(0), 141.7(0), 128.8(1), 128.7(1), 114.7(1), 114.5(1), 72.9(2), 56.5(0), 48.4(3), 34.3(2), 26.6(2), 22.1(2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18]C(=O)C)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO>O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]1)[CH3:22])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
To a cooled (˜15° C.) and stirred solution of 18 g (57.4 mmol) of trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester in 135 ml of dioxane was added 63.2 mL (63.2mmol, 1.1 eq) of aqueous 1 M NaOH within 5 min. The reaction was homogenised with 13 mL of MeOH and 28.7 mL (28.7 mmol, 0.5 eq) of aqueous 1 M NaOH after 3 h, then stirred for additional 1.5 h. The reaction was evaporated to remove the dioxane, partitioned between Et2O (×3)/H2O, dried over Na2SO4 and evaporated to yield 17.13 g (quantitative) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester, MS: 272 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3coc(-c4ccccc4)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3coc(-c4ccccc4)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]#[N:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:30]([C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]2[C:41]([CH2:42][OH:43])=[C:40]([Cl:44])[N:39]=[C:38]2[CH2:45][CH2:46][CH2:47][CH3:48])=[CH:34][CH:33]=1)=O.C[O-].[Na+]>CN(C)C=O.O>[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1/[CH:2]=[CH:30]/[C:32]1[CH:33]=[CH:34][C:35]([CH2:36][N:37]2[C:41]([CH2:42][OH:43])=[C:40]([Cl:44])[N:39]=[C:38]2[CH2:45][CH2:46][CH2:47][CH3:48])=[CH:49][CH:50]=1)#[N:10]
Reactant: N#Cc1ccccc1CBr
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(/C=C/c2ccccc2C#N)cc1
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a solution of 0.98 g of α-bromo-o-tolunitrile in 25 mL of dimethylformamide at 25° was added 1.40 g of triphenylphosphine. The mixture was stirred at 80° for 3 hours, then treated with 1.53 g of 1-(4-formylbenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole, followed immediately by 0.54 g of sodium methoxide, and the mixture was diluted with water and extracted with benzene. The organic phases were combined and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) afforded 0.45 g of 1-[(2'-cyano-trans-stilben-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole; NMR (200 MHz, CDCl3): δ8.01 (d, 1h); 7.85 (d, 1h); 7.73 (t, 1h); 7.47 (t, 1h); 7.44 (AB, 2H, J=16.3); 7.38 (A2B2, 4H); 5.28 (s, 2H); 5.24 (t, 1H); 4.34 (d, 2H); 2.49 (t, 2H); 1.47 (quint., 2H); 1.24 (sext., 2H); 0.79 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.C([Li])CCC.[C:13](=[O:15])=[O:14].Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: O=C=O
Reactant: COc1ccsc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccsc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methoxythiophene (4.81 g, 42.1 mmol) in ether (20 mL) at -78° C., butyllithium (17 mL, 47.6 mmol) was added. The reaction mixture was stirred at -78° C. for 1 hour, then it was warmed to 0° C. for 3 hours. After to recooling -78° C. the reaction mixture was poured into a beaker filled with crushed dry ice (14.5 g) and allowed to stand until the excess dry ice had completely sublimed. Then the reaction mixture was poured into a mixture of ice (10 g) to which conc. HCl (24 mL) had been added. The product was purified by precipitation from ether and filtering (6.42 g, 96%). EI-MS m/z 159 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:22])[N:3]=1.[CH3:23][O-:24].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:24][CH3:23])[C:5]([CH2:9][N:10]([CH3:21])[C@@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1CN(C)[C@H]1CCCc2ccccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc(C)c1CN(C)[C@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flask containing (1S)-(2,4-dichloro-6-methyl-pyrimidin-5-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (6.41 g, 19.06 mmol) is added MeOH (100 mL) and the solution is cooled to 0° C. using an ice bath. NaOMe (0.5 M, 38 mL) is added via addition funnel over 20 min. Once addition is complete, the ice bath is removed and the reaction is allowed to proceed overnight warming to room temperature. HOAc (2.0 mL) is added and the reaction mixture is allowed to stir for 10 min, followed by concentration at reduced pressure. The resulting oil is dissolved in EtOAc (100 mL) and washed sat. NaHCO3 (100 mL), brine (100 mL) and dried over Na2SO4. Flash chromatography on SiO2 using first CHCl3 followed by 20:1 hexanes:Et2O affords the title compound as a colorless oil. [mass expected (331.84); mass found (331.28)]
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].BrC1C=CC(Cl)=CC=1[CH2:21][O:22][CH2:23]OC>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[CH2:4][O:5][CH2:21][O:22][CH3:23]
Reactant: COCOCc1cc(Cl)ccc1Br
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Product: COCOCc1cc(F)c(F)cc1Br

Procedure:
This compound was made from 2-bromo-4,5-difluorobenzoic acid in the same manner as compound 18d: 1H NMR (300 MHz, CDCl3) δ (ppm) 3.42 (s, 3H), 4.57 (d, J=1.2 Hz, 2H), 4.76 (s, 2H), 7.3-7.5 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH2:15])([O-])=O.Cl.C(O[C:20](=N)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C>CCO.[Pd]>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]1[CH:7]=[CH:6][C:5]2[N:15]=[C:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:1][C:4]=2[CH:9]=1
Reactant: CCOC(=N)CC(=O)OCC
Reactant: Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccc(-c3cccs3)cc2[nH]1
Reaction time: 3 h

Procedure:
2-Nitro-4-(2-thienyl)phenylamine (1.0 equivalent) and 10% Pd/C (0.1 equivalents) were suspended in anhydrous EtOH at room temperature. The reaction flask was evacuated and subsequently filled with H2. The resulting mixture was allowed to stir under a hydrogen atmosphere for 3 hours. Ethyl 3-ethoxy-3-iminopropanoate hydrochloride (2.0 equivalents) was then added and the resulting mixture was heated at reflux for 12 hours. After this time, the solution was filtered through a plug of Celite, concentrated, dissolved in 50 mL of 2 N HCl and washed with CH2Cl2. The aqueous layer was brought to pH 12 with concentrated NH4OH(aq) and extracted with CH2Cl2. The combined organic layers were dried with MgSO4 and concentrated to yield a brown oil which was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to provide a yellow solid. LC/MS m/z 287.1 (MH+), Rt 1.98 minutes.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccccn3)ncc12
Temperature: 110 °C
Yield: 30 %

Procedure:
A mixture of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (370 mg, 1 mmol, prepared as in Example 6 of WO 01/707041 which is incorporated here by reference) and 2-aminopyridine(140 mg, 1.5 mmol) in toluene (5 mL) was heated at 110° C. for 18 hours then cooled to room temperature. The solid formed was collected by filtration and washed with toluene, then acetone, and dried in vacuo to give 6-bromo-8-cyclopentyl-5-methyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a beige solid (22 mg, 30%). mp 267–268° C. Anal. Calc'd. for C18H18BrN5O.0.33H2O: C, 53.22; H, 4.63; N, 17.24. Found: C, 52.88; H, 4.38; N, 17.04.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C.[Cu](I)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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1nc(Br)cnc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(N)c(C#N)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.0 grams (0.015 mole) of 2-amino-3-cyano-5-bromopyrazine and 2.1 grams (0.021 mole) of trimethylsilylacetylene in 50 mL of acetonitrile is stirred, and 10.6 mL of triethylamine, 0.13 gram of copper iodide, and 0.29 gram of bis(triphenylphosphine)palladium(II) chloride are added in order. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. The reaction mixture is warmed to 70° C., where it is stirred for about 7.5 hours. After this time, the reaction mixture is concentrated under reduced pressure to a residue. The residue is dissolved in ethyl acetate, and the solution is washed with 50 mL of aqueous, dilute hydrochloric acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. Elution is accomplished using tetrahydrofuran/methylene chloride combinations. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-(trimethylsilylethynyl)pyrazine.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([NH:22][CH:23]=[NH:24])[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:21])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:8]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>O1CCOCC1>[CH3:3][C:4]1[N:5]2[C:6]([C:25](=[O:26])[NH:24][CH:23]=[N:22]2)=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:21])[C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[N:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-c2c(-c3cn(NC=N)c(C)n3)cnn2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(-c3nc(C)n4nc[nH]c(=O)c34)cnn2C)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 24 mg, 0.60 mmol) was added to a solution of N-{2-methyl-4-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-1H-imidazol-1-yl}imidoformamide (70 mg, 0.24 mmol) in 1,4-dioxane (4.0 mL), and the mixture was heated at 75° C. for 10 minutes. The reaction was cooled, treated with 1,1′-carbonyldiimidazole (135 mg, 0.833 mmol), allowed to stir at room temperature for 30 minutes, and then heated to 100° C. for 18 hours. After the reaction cooled to room temperature, it was quenched with water and diluted with ethyl acetate. The organic layer was washed with water, then with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 10% methanol in ethyl acetate) afforded the product as a white solid. Yield: 55 mg, 0.17 mmol, 71%. LCMS m/z 321.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 2.34 (br s, 3H), 2.36 (s, 3H), 3.71 (s, 3H), 7.22 (br d, J=8 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.79 (s, 1H), 7.95 (s, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[N:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)=[N:7][CH:8]=1
Reactant: Cc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
5-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (507 mg, 1.6 mmol, from Example 44, Step 5), phenyl pyridazin-3-ylcarbamate (430 mg, 2.0 mmol) and triethylamine (0.892 mL, 6.4 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10%, MeOH:CH2Cl2) to afford the title compound (526 mg) as a foamy white solid. MS APCI M+ 402.1, 281.2 M− 400.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.29 (s, 3H) 2.46 (td, J=5.71, 0.93 Hz, 2H) 2.58 (td, J=5.74, 1.06 Hz, 2H) 3.52-3.61 (m, 2H) 3.65-3.71 (m, 2H) 6.44 (s, 1H) 6.85 (dd, J=8.41, 0.33 Hz, 1H) 6.89-6.96 (m, J=4.21, 4.21, 2.47, 1.01 Hz, 2H) 7.04-7.11 (m, J=7.63, 1.41, 1.04, 0.83 Hz, 1H) 7.31-7.42 (m, 1H) 7.59 (dd, J=9.09, 4.70 Hz, 1H) 7.66 (ddd, J=8.39, 2.49, 0.66 Hz, 1H) 7.97 (td, J=1.63, 0.77 Hz, 1H) 8.12 (d, J=9.32 Hz, 1H) 8.79 (d, J=4.37 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccc(Cl)c1N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 32.8 %

Procedure:
A 100 mL round-bottom flask was charged with 3-chloro-2-fluorobenzaldehyde (3.00 g, 18.9 mmol, 1.00 equiv), morpholine (2.50 g, 28.7 mmol, 1.52 equiv), potassium carbonate (6.50 g, 47.0 mmol, 2.49 equiv), and dimethyl sulfoxide (30 mL). The resulting solution was stirred for 3 hours at 100° C. in an oil bath and diluted with H2O (30 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/20) to provide 1.40 g (33% yield) of 3-chloro-2-(morpholin-4-yl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 226 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[CH3:16][C:17]1[N:21]([CH:22](S(OC)(=O)=O)[CH3:23])[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][CH:18]=1>CN(C)C=O.O>[CH3:16][C:17]1[N:21]([CH2:22][CH2:23][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COS(=O)(=O)C(C)n1c(C)ccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2)n1CCOc1ccc(C=O)cc1
Reaction time: 4 h

Procedure:
To a suspension of potassium carbonate (16.43 g) in dimethyl formamide (50 mL), 4-hydroxy benzaldehyde (4.37 g) was added and warmed to 90° C. to 95° C. To the solution, methyl 1-[5-methyl-2-phenyl-1H-pyrrol-1yl]ethane sulfonate (10 g) (compound no. 41) dissolved in dimethyl formamide (50 mL) was added within 30 min and the reaction was continued for further 4 hours. The reaction mixture was diluted with water (100 mL) and was extracted with ethyl acetate (3×100 mL), washed with water (3×100 mL), brine (200 mL), and was dried over sodium sulfate. The solvent was evaporated under reduced pressure, to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=O)[CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:16])[CH:12]=[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(C)Nc1ccccc1
Reaction time: 1 h

Procedure:
Aniline (0.20 mol) and ethylacetoacetate (0.20 mol) are mixed in toluene (200 mL) containing 0.04 g of p-toluenesulfonic acid-hydrate and heated at reflux under a water separator for one hour. The toluene is removed under vacuum to afford the ethyl-3-phenylaminobut-2-enoate which can be used as is for the preparation of the ethyl 2-methyl-3-quinolinecarboxylate.
Reaction SMILES: [C:1]12([C:14]([O:16]C)=[O:15])[CH2:9][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2>C(O)C.O>[CH3:13][O:12][C:10]([C:5]12[CH2:9][C:1]([C:14]([OH:16])=[O:15])([CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2)=[O:11]
Reactant: COC(=O)C12CCCC(C(=O)OC)(CCC1)C2
Solvent: CCO
Solvent: O
Product: COC(=O)C12CCCC(C(=O)O)(CCC1)C2
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A solution of dimethyl bicyclo[3.3.1]nonane-1,5-dicarboxylate (8.32 g, 36.8 mmol) and Ba(OH)2.8H2O (5.80 g, 18.4 mmol) in ethanol (40 mL) and H2O (10 mL) was refluxed overnight. After cooled to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was added diluted with water (100 mL) and extracted with diethyl ether (3×200 mL). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated under reducer pressure to recover starting material as an orange oil. The aqueous phase was adjusted to pH 1˜2 with 2N aq. HCl, and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 1.8 g (67%) of 5-(methoxycarbonyl)bicyclo[3.3.1]nonane-1-carboxylic acid as a white solid. ESI-MS m/z: 213 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)[CH3:2].Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH3:2]
Reactant: CCOC(=O)CC(CCCCCCCNC(=O)OC(C)(C)C)c1cnc(C)nc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(CCCCCCCN)c1cnc(C)nc1
Yield: 104.8 %

Procedure:
A solution of 24-6 (495 mg, 1.21 mmol) in ethyl acetate (3 mL) was treated with a saturated solution HCl in ethyl acetate (10 mL) at room temperature overnight. The solvent was removed in vacuo to afford 24-7 (390 mg). The crude product was used directly in the next reaction.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:24]([O-])([OH:26])=[O:25].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[N+:24]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][N:8]2[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([O-:26])=[O:25]
Reactant: COC(=O)Cc1cnc(-c2ccccc2)n1Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)Cc1cnc(-c2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 20 ml of glacial acetic acid was dissolved 1.2 g of methyl 1-benzyl-2-phenylimidazole-5-acetate, and 20 ml of fuming nitric acid (specific gravity of 1.52) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction solution was poured into 1 l of ice water, neutralized with sodium bicarbonate, and extracted with three 100 ml portions of ethyl acetate. The ethyl acetate layers were combined and evaporated to dryness under reduced pressure, followed by chromatographing on a column of 50 g of silica gel to thereby elute with benzene-ethyl acetate (1:1). The fractions of the objective compound were collected and evaporated to dryness under reduced pressure, yielding 1.25 g of methyl 1-(4-nitrobenzyl)-2-phenylimidazole-5-acetate as colorless crystals. Recrystallization of a part of the compound from benzene-hexane afforded the crystals, m.p. 113°-116° C.