Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Br:8])[N:7]=1.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].S(OCC)(O[CH2:22][CH3:23])(=O)=O>O>[CH2:22]([N:4]1[CH:5]=[C:6]([Br:8])[N:7]=[C:2]([Br:1])[C:3]1=[O:9])[CH3:23]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=c1[nH]cc(Br)nc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(Br)nc(Br)c1=O
Reaction time: 15 h
Yield: 66.8 %

Procedure:
6.2 g of 3,5-dibromo-pyrazin-2-one are suspended in a mixture of 38 ml of water, 11.1 ml of 2 N sodium hydroxide solution and 0.5 g of sodium carbonate. 4.3 g of diethyl sulfate are then added dropwise at 20°-25° C. and the mixture is subsequently stirred at the same temperature for 15 hours. The product is filtered off at 0° C., washed with ice-water and dried to give 4.6 g of 1-ethyl-3,5-dibromo-pyrazin-2-one.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:22]([F:25])([F:24])[F:23])=[O:19])=[CH:12][C:11]=1[C:36]([F:39])([F:38])[F:37].CCN(C(C)C)C(C)C>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)[C:22]([F:23])([F:24])[F:25])=[O:19])=[CH:12][C:11]=1[C:36]([F:37])([F:38])[F:39])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: NCc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30 mg (1.2 eq, 0.28 mmol) of isobutyryl chloride were dissolved in 1 ml of dichloromethane. To this were added 113 mg (1.0 eq, 0.24 mmol) of the hydrochloride of (2E)-3-[4-(aminomethyl)-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl)acrylamide from Stage 5 and 93 mg (3 eq) of Hünig's base. The mixture was stirred at room temperature for 16 h then concentrated. The crude product was purified by means of preparative HPLC (Phenomenex Gemini C18 5 μm; 125A; Aqua 50×21.2 mm; gradient: 0-1.5 min 78% water, 20% acetonitrile, 1.5-10.0 min linear gradient to 18% water, 80% acetonitrile, 10.0-14.00 min 18% water, 20% acetonitrile; modifier: 10% NH4HCO3 added at 2 ml/min). This gives 57 mg (44%) of (2E)-3-{4-[(isobutyrylamino)methyl]-3-(trifluoroethyl)phenyl}-N-{2,2,2-trifluoro-1-[3-(trifluoro-methyl)phenyl]ethyl}acrylamide.
Reaction SMILES: C(OC1C=C(C2CCNCC2)C(C)=CC=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)(C)C.BrCCOC.C(N(CC)CC)C>>[CH:39]([S:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:21]1[N:20]=[C:19]([NH2:18])[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]=12)(=[O:37])=[O:38])([CH3:41])[CH3:40]
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Agent: COCCBr
Solvent: CCN(CC)CC
Product: Cc1n[nH]c2nc(N)nc(Nc3ccccc3S(=O)(=O)C(C)C)c12
Temperature: 100 °C

Procedure:
The mixture of N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (26.6 mg, 0.046 mmol), 1-bromo-2-methoxyethane (1.0 N in DMF, 0.46 mmol, 0.46 mL), and triethylamine (1.0 N in DMF, 0.46 mmol, 0.46 mL) was heated at 100° C. for 10 min The resulting reaction mixture was purified by RP-HPLC to afford N6-(2-isopropoxy-4-(1-methoxyethyl)piperidin-4-yl)-5-methylphenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine. MS (ES+): 636.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.CN1C(=O)CCC1.[F:28][C:29]([F:37])([F:36])[C:30]([F:35])([F:34])C([O-])=O.[Na+].C(=O)([O-])O.[Na+]>[Cu](I)I.C1(C)C(C)=CC=CC=1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:30]([F:35])([F:34])[C:29]([F:37])([F:36])[F:28])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Temperature: 170 °C
Yield: 7.7 %

Procedure:
A mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (500 mg), NMP (24 ml), xylene (10 ml), copper iodide (1.1 g), and sodium pentafluoropropionate (1.1 g) was heated to 170° C., and stirred with heating for 3 days. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with tert-butyl methyl ether. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 43 mg of 2-(2-ethylsulfanylphenyl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 55).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].C1(=O)N(CCS(Cl)(=O)=O)C(=O)C2=CC=CC=C12.N1C=CC=CC=1.[O:57]=[C:58]([S:72](Cl)(=[O:74])=[O:73])[CH2:59][N:60]1[C:64](=[O:65])[CH:63]2[C:66](=[O:70])[CH:67]=[CH:68][CH:69]=[C:62]2[C:61]1=[O:71]>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[S:72]([C:58](=[O:57])[CH2:59][N:60]1[C:64](=[O:65])[CH:63]2[C:66](=[O:70])[CH:67]=[CH:68][CH:69]=[C:62]2[C:61]1=[O:71])(=[O:73])=[O:74])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: O=C1C=CC=C2C(=O)N(CC(=O)S(=O)(=O)Cl)C(=O)C12
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)C(=O)CN1C(=O)C2=CC=CC(=O)C2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 8 ml of dichloromethane was treated with 0.287 g of 2-phthalimidoethanesulphonyl chloride and 0.1 ml of pyridine at room temperature under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature and a further 0.287 g of 1,3-dioxo-2-phthalimidoethanesulphonyl chloride was added. The mixture was stirred overnight at room temperature and evaporated. The residue was dissolved in ethyl acetate and washed in sequence with water, 5% aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate and evaporation gave a residue which was triturated with diethyl ether to give 0.47 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(1,3-dioxo-2-phthalimidoethanesulphonyl)-4-methylvalerohydrazide in the form of a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.Cl.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2
Reactant: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 mmol of 2-(4-((6-fluoro-2-quinolinyl)oxy)phenoxy)propionyl chloride in 5 milliliters (ml) of methylene chloride was slowly added to an ice-cooled solution comprising 1.17 grams (g) (5.5 mmol) of 4-(trifluoromethoxy)aniline hydrochloride and 1.21 g (12 mmol) of triethylamine in 40 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 30 minutes then at room temperature for 3 hours. The mixture was poured into a dilute aqueous HCl solution. The organic layer was separated, washed with water, then washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was taken up in methylene chloride and filtered through a short column of silica gel, eluting with additional methylene chloride. After removal of the solvent, the residue was recrystallized from methylcyclohexane to give 1.0 g (41 percent of theoretical) of the above-named product as colorless crystals. The product melted at 134°-136° C. and its structure was confirmed by its infrared (IR) and its nuclear magnetic resonance (NMR) spectrum. (Compound 3)
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[N:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3.[SH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.O>C(O)C.[OH-].[Na+]>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][S:15][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[N:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: Clc1nc2cc3ccccc3cc2[nH]1
Reactant: SCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1
Yield: 51.4 %

Procedure:
0.92 g of 2-chloro-1H-naphth[2,3-d]imidazole and 0.57 g of 2-mercaptomethylpyridine were heated under reflux for 18 hours in 15 ml of ethanol and 4.5 ml of 1 N caustic soda. 50 ml of water were added to the reaction solution, which was then extracted twice with a total amount of 50 ml of ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, and evaporated to dryness on a rotary evaporator. Crystallisation from 50 ml of acetonitrile provided 0.68 g of 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a m.p. of 169°-170°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]3[C:15](=[O:23])[O:16][C:17]([CH3:22])([C:19]([OH:21])=[O:20])[CH2:18][C:13]=3[N:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:24][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH3:24][O:20][C:19]([C:17]1([CH3:22])[O:16][C:15](=[O:23])[C:14]2[N:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)[CH:11]=[N:12][C:13]=2[CH2:18]1)=[O:21]
Reactant: CC1(C(=O)O)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(C)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To 50 mg (0.15 mmol) of 44 in 2 mL of a 1:1 CH2Cl2/MeOH is added 0.07 mL (0.14 mmol) of 2 M trimethylsilyl diazomethane in hexanes. After stirring for 1 h another 0.07 mL (0.14 mmol) of 2M trimethylsilyl diazomethane is added. The mixture is stirred for 1 h, concentrated, dissolved in 50 mL of EtOAc, and washed with twice with 20 mL of H2O and once with 20 mL of brine. The organic phase is dried with MgSO4, filtered, and concentrated to give 21 mg (0.06 mmol) of 45.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:61][CH3:62])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[CH:41]([CH3:40])[CH2:61][CH3:62])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 36E (0.020 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate, to give the title compound (0.026 g, 68% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (m, 18 H), 1.16 (m, 1 H), 1.29 (m, 1 H), 1.52 (m, 1 H), 1.76 (s, 1 H), 2.39 (s, 3 H), 2.68 (m, 4 H), 3.20 (m, 2 H), 3.50 (s, 3 H), 3.83 (m, 2 H), 4.13 (m, 2 H), 4.67 (m, 2 H), 6.66 (d, J=9.56 Hz, 1 H), 7.07 (m, 7 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.66 (t, J=7.72 Hz, 1 H), 7.86 (m, 6 H), 8.63 (d, J=4.04 Hz, 1 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH3:9][C:10]1[O:14][N:13]=[CH:12][C:11]=1[C:15](Cl)=[O:16]>O>[CH3:9][C:10]1[O:14][N:13]=[CH:12][C:11]=1[C:15]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: Cc1oncc1C(=O)Cl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1oncc1C(=O)N1CCCCC1

Procedure:
0.4 mol (34.1 g) of piperidine and 40 ml of 10N sodium hydroxide solution are added dropwise to 0.4 mol (58.2 g) of 5-methyl-4-isoxazolecarboxylic acid chloride, emulsified in 300 ml of water, such that the temperature of the reaction mixture does not rise above 35° C. 40 ml of 2N sodium hydroxide solution are then added and the mixture is extracted with 300 ml methylene chloride. The aqueous phase is extracted once more by shaking with 200 ml of methylene chloride. The combined methylene chloride phases are washed with water and, after drying over sodium sulfate, evaporated to dryness under reduced pressure. N-(5-Methyl-4-isoxazolylcarbonyl)-piperidine is thus obtained, the product having, after recrystallization from methylcyclohexane, a melting point of 40° to 43° C.
Reaction SMILES: C(C1C=C(C)C(CNC)=C(C)C=1O)(C)(C)C.C(C1C=C(C)C(CNCCO)=C(C)C=1O)(C)(C)C.[C:35](Cl)(=O)[C:36]1[C:37](=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:38]([Cl:40])=[O:39].[C:47](Cl)(=O)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56](Cl)=O>>[C:38]([Cl:40])(=[O:39])[CH2:37][CH2:41][CH2:42][CH2:43][CH2:44][CH2:36][CH2:35][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: CNCc1c(C)cc(C(C)(C)C)c(O)c1C
Agent: Cc1cc(C(C)(C)C)c(O)c(C)c1CNCCO
Product: CCCCCCCCCCCCCCCCCC(=O)Cl

Procedure:
By an analogous procedure to that described in the first part of Example 16 and using 6-tert.-butyl-3-(N-methylaminomethyl)-2,4-xylenol (produced as described in the first part of Example 22) in place of 6-tert.-butyl-3-[N-(2-hydroxyethyl)aminomethyl]-2,4-xylenol and phthalic acid dichloride and sebacic acid dichloride, respectively, in place of stearoyl chloride, the following compounds, respectively, are produced: ##STR69##
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:6]([Cl:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(O)=[O:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:14][C:6]1[C:5]([CH2:4][CH2:1][OH:2])=[CH:13][CH:12]=[CH:11][C:7]=1[CH:8]=[O:9]
Reactant: O=C(O)Cc1cccc(C(=O)O)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc(CCO)c1Cl

Procedure:
Manganese (IV) dioxide (43.1 g) was added to a slight suspension of 2-(2-chloro-3-(hydroxymethyl)phenyl)ethanol [Aromatic Intermediate 11, step d] (18.5 g) in chloroform (500 mL), and the resulting suspension was heated at reflux for 2 h. The reaction mixture was cooled, filtered through Celite and the filter pad washed with DCM (3×300 mL). The combined washings and filtrate were evaporated and the residue purified by flash silica chromatography eluting with 3:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the titled compound as a white solid. Yield 12.00 g.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=1)([CH3:9])[CH3:8].CI>CC(C)=O>[CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([O:18][CH3:1])=[O:17])[CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1ccn(CC(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)Cn1ccc(C(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
Potassium carbonate (298 mg, 2.15 mmol) was added to a solution of 2-(3-isopropylpyrrol-1-yl)acetic acid (180 mg, 1.07 mmol) in acetone at 0° C. and the reaction was stirred at 0° C. for 15 min. Methyl iodide (0.13 mL, 2.15 mmol) was added at 0° C. and the mixture refluxed for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to give the crude compound. Purification by column chromatography over neutral alumina by using 1-2% ethyl acetate in petroleum ether as eluent afforded methyl 2-(3-Isopropylpyrrol-1-yl)acetate (135 mg, 69%) as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Br)cc1C
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C(=O)OC
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy)-nicotinic acid methyl ester and 1-ethyl-propyl-amine in DMSO was heated at 120° C. for 16 hr. The mixture was quenched with water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography using hexane to 3% ethyl acetate in hexane as eluent to give to the title compound as a white solid. 1H NMR(CDCl3) d 8.1(d, 1H), 7.18(s, 2H), 6.08(s, 1H), 3.87(s, 3H), 3.35(m, 1H), 2.10(s, 3H), 2.08(s, 6H), 1.4-1.7(m, 4H), 0.96(t, 6H) ppm.
Reaction SMILES: Cl.[C:2]1([CH2:8][NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[N:13]=[CH:12][C:11]=2[NH:20][C:21](=O)[CH2:22][O:23][CH2:24][CH3:25])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>CO>[CH2:24]([O:23][CH2:22][C:21]1[N:9]([CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=1)[CH3:25]
Reactant: CCOCC(=O)Nc1cnc2cccnc2c1NCc1ccccc1
Agent: Cl
Agent: N
Solvent: CO
Product: CCOCc1nc2cnc3cccnc3c2n1Cc1ccccc1
Temperature: 150 °C

Procedure:
N-(4-Phenylmethylamino[1,5]naphthyridin-3-yl)-ethoxyacetamide hydrochloride (5.8 g, 15.5 mmol) was combined with a 7 % solution of ammonia in methanol (100 mL), placed in a sealed Parr vessel and then heated at 150° C. for 6 hours. The reaction mixture was concentrated under vacuum. The residue was partitioned between water and dichloromethane. The dichloromethane layer was separated, washed with water, dried over magnesium sulfate and then concentrated under vacuum. The residue was recrystallized from methyl acetate to provide 4.3 of 2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine, m.p. 118-119° C. Analysis: Calculated for C19H18N4O: %C, 71.68; %H, 5.70; %N, 17.60; Found: %C, 71.44; %H, 5.60; %N, 17.66.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:18])[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and butanoyl chloride (266 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:1). The fractions containing 1-(4-benzylpiperazin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 432 mg of colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[I:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>ClCCl.N1C=CC=CC=1>[I:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([I:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(I)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(I)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc(I)c1
Yield: 7.3 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (3.00 g, 8.74 mmol) in 75 mL of dichloromethane and 3-iodoaniline (3.82 g, 17.5 mmol) in 17 mL of pyridine. The crude product was triturated with hot ethanol, filtered, and recrystallized first from water-DMF, then from ethyl acetate-ether to yield 0.45 g of the title compound, mp 184°-186° C. (dec.).
Reaction SMILES: C12(C[O:12]C3C=CC(C#N)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[C:29]12([CH2:39][O:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][C:42]=3[Br:49])[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2>>[C:29]12([CH2:39][O:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]([NH2:46])=[O:12])=[CH:43][C:42]=3[Br:49])[CH2:30][CH:31]3[CH2:37][CH:35]([CH2:34][CH:33]([CH2:32]3)[CH2:38]1)[CH2:36]2
Reactant: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1
Reactant: COc1ncccc1-c1cc(C#N)ccc1OCC12CC3CC(CC(C3)C1)C2
Product: NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1

Procedure:
Following the procedure as described in Example 38 step 3 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzonitrile with 4-(adamantan-1-ylmethoxy)-3-bromobenzonitrile, the title compound was obtained as a colorless solid (1.80 g, 98%): 1H NMR (300 MHz, CDCl3) δ 7.99-7.97 (m, 1H), 7.74-7.69 (m, 1H), 6.87-6.83 (m, 1H), 5.86 (br s, 2H), 3.57 (s, 2H), 2.02 (br s, 3H), 1.79-1.58 (m, 12H); MS (ES+) m/z: 364.1, 366.1 (M+1).