Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:18])[C:11](=[O:17])[N:12]2[CH2:15][CH3:16])=[CH:7][CH:6]=1)(=O)C.[N+:19]([O-])([O-:21])=[O:20].[Na+].[OH-].[Na+].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:18])[C:11](=[O:17])[N:12]2[CH2:15][CH3:16])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])[O-]
Reactant: CCn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
5.2 g (21 mmol) of 7-acetamido-1-ethyl-2,3(1H,4H)-quinoxalinedione were dissolved in 75 ml of concentrated sulfuric acid and, at 0°-5° C., 2 g (23 mmol,) of sodium nitrate were added. The mixture was stirred at 0°-5° C. for 2 h and then poured into ice-water and stirred at room temperature for 16 h. The mixture was then neutralized with dilute sodium hydroxide solution and sodium bicarbonate solution and concentrated under reduced pressure. The residue was extracted with dimethylformamide and then the organic phase was concentrated anew. The residue was purified on silica gel (mobile phase: toluene/acetone/acetic acid=10:10:1) to yield 1.2 g (23%) of the product.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[NH:12]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[OH-].[K+].I[CH:21]([CH3:23])[CH3:22].O>C(#N)C>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:11]=3[NH:12]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc2c(cc1F)[nH]c1ccccc12
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(C)c1cccc2c1[nH]c1cc(F)c([N+](=O)[O-])cc12
Reaction time: 8 h
Yield: 42.9 %

Procedure:
3-Fluoro-benzohydrazine (3.3 g) and cyclohexanone (2.2 g) were added to ethanol (30 ml) and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the resulting residue was recrystallized from hexane to obtain 7-fluoro-carbazole (1.81 g, 48%). Then, concentrated sulfuric acid (20 ml) was cooled to 0° C. and added with 7-fluoro-carbazole (2.1 g) and sodium nitrate (900 mg), and then the mixture was stirred for 10 minutes. The reaction mixture was poured on an ice layer and filtered to obtain 7-fluoro-6-nitro-carbazole (1.1 g, 42%). The resulting 7-fluoro-6-nitro-carbazole (500 mg) and KOH (200 mg) were stirred in acetonitrile as a solvent, and then the mixture was added dropwise with 2-iodopropane (500 mg) and stirred for 8 hours. The reaction mixture was added with water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 7-fluoro-1-isopropyl-6-nitro-carbazole (254 mg, 43%). The resulting 7-fluoro-1-isopropyl-6-nitro-carbazole (500 mg) and Fe (400 mg) were stirred in i-PrOH/water solvent (1:1) under reflux. The reaction mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain 6-amino-7-fluoro-isopropyl-carbazole (290 mg, 65%). The resulting amino compound (500 mg) was dissolved in chloroform (10 ml), and the solution was added dropwise with phenyl chloroformate (190 mg) and stirred for 2 hours. The reaction mixture was added with water and extracted. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (adsorbent: silica gel, developing solvent: ethyl acetate/hexane) to obtain phenylurethane (263 mg, 61%).
Reaction SMILES: [NH:1]([C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].[Na]>>[C:22]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: OCCCCCCOc1ccc(Nc2ccccc2)cc1
Reactant: COC(=O)C(C)(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Agent: [Na]
Product: CC(C)(C)C(=O)OCCCCCCOc1ccc(Nc2ccccc2)cc1
Temperature: 88 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(p-anilinophenoxy)hexanol (28.5 g.) and methyl pivalate (34.5 g.) to which 0.3 g. of aluminum isopropylate and a small chip of sodium metal had been added was heated at 88° C. while stirring for about 3 hours. Gas chromatography indicated that transesterification was not complete. Methyl pivalate was distilled from the reaction allowing the temperature to rise to 160° C. and was then added slowly back to the mixture at such a rate that the temperature could be maintained at 175°-185° C. After two hours, the reaction mixture was stripped of volatiles by heating at 120° C. under reduced pressure (150 mm of mercury). The solid residue obtained on cooling was recrystallized from 2-propanol to afford the ester, 6-(p-anilinophenoxy)hexyl pivalate as a crystalline solid, m.p. 64°-65° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:12][CH2:11]1)=[O:8]
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and methanesulphonyl chloride (0.125 mL, 1.6 mmol). The reaction mixture was stirred overnight at room temperature, and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water and dried (MgSO4). The dessicant was filtered off and the resulting solution was treated with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to dryness. Column chromatography of the crude product using DCM/MeOH 95:5 as eluent gave 2-(2,4-Dichloro-phenoxy)-N-(1-methanesulfonyl-piperidin-4-yl)-benzamide (86 mg, 72%) as a white solid. LC/MS (APCI) tr=4.56 min, m/z 445.32 (65), 443.31 (M++H, 100). HPLC tr=3.42 min (97.52%) 1H NMR (270 MHz, CDCl3) 1.56-1.69 (2H, m, CH2), 2.06 (2H, m, CH2), 2.75 (3H, s, CH3), 2.86 (2H, m, CH2), 3.68 (2H, m, CH2), 4.09 (1H, m, CH), 6.79 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.88 (1H, d, J=8.9 Hz, ArH), 7.20-7.28 (2H, m, ArH), 7.38-7.42 (2H, m, ArH+NH), 7.51 (1H, d, J=2.5 Hz, ArH) and 8.15 (1H, dd, J=7.9, 2.0 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 31.47 (CH2), 34.83 (CH3), 44.96 (CH2), 46.28 (CH), 117.76, 120.77, 124.32, 124.83, 125.88, 128.59, 130.44, 130.88, 132.56, 133.04, 149.79, 153.56 (ArC), and 163.97 (C═O).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.N.[N+:25]([O-])([OH:27])=[O:26]>S(=O)(=O)(O)O>[N+:25]([C:10]1[CH:11]=[CH:12][C:7]2[N:6]3[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]3[C@@H:4]3[CH2:21][CH2:22][CH2:23][N:3]3[C:2](=[O:1])[C:8]=2[CH:9]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Agent: N
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C

Procedure:
A solution of 3.11 g of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate in a mixture of 10 ml of 98 percent nitric acid and 15 ml of 98 percent sulphuric acid is heated to 100° for 6 hours. Subsequently, the mixture is cooled to room temperature, poured onto ice, neutralized with about 25 percent ammonia and extracted with chloroform. The chloroform extracts are dried over magnesium sulphate and evaporated. The residue is recrystallized from ethyl acetate and yields ethyl (S)-11,12,13,13a-tetrahydro-7-nitro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 193°-194°.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[CH:12]=[O:13]>O.CC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[C:12]([OH:2])=[O:13]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Yield: 71.6 %

Procedure:
To a solution of potassium permanganate (3.05 g) in water (100 ml) was added to a solution of 3,4-dimethoxy-5-nitrobenzaldehyde (2.7 g) in acetone (80 ml). The mixture was then stirred at 20° for 18h whereupon the acetone was evaporated and the residue acidified (2N HCl) and was then decolourised by the addition of sodium metabisulphite sodium. The mixture was then extracted with ethyl acetate (3×200 ml) and the dried extracts evaporated to give the title compound as a colourless solid (2.08 g) m.p. 197°-198°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[C:11](=[O:21])[O:10][N:9]=2)=[N:5][O:6][N:7]=1.CCN(C(C)C)C(C)C.[Cl:31][CH2:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:31][CH2:32][CH2:33][CH2:34][S:35]([NH:1][CH2:2][C:3]1[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)[C:11](=[O:21])[O:10][N:9]=2)=[N:5][O:6][N:7]=1)(=[O:37])=[O:36]
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1onc(-c2nonc2CNS(=O)(=O)CCCCl)n1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.7 %

Procedure:
To a solution of 3-[4-(aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (100 mg, 0.32 mol) in DCM (2 mL) under an atmosphere of nitrogen was added DIPEA (168 μL, 0.96 mmol), and 3-chloropropane-1-sulfonyl chloride (117 μL, 0.66 mmol). The reaction was stirred at 25° C. for 5 min. The reaction was quenched with MeOH and purified by preparative HPLC to yield the desired product (38 mg, 20%). 1H NMR (400 MHz, CDCl3): δ 7.5 (m, 1H), 7.3 (m, 2H), 4.8 (d, 2H), 3.7 (t, 2H), 3.25 (t, 2H), 2.3 (m, 2H). MF═C14H12Cl2FN5O5S; LCMS calculated for C14H13Cl2FN5O5S(M+H)+: m/z=452.2
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)(C(OC(C)(C)C)=O)[C:9]([O:11][C:12](C)(C)C)=[O:10])=[CH:3][CH:2]=1.Cl.C(OCC)(=O)C>FC(F)(F)C(O)=O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([CH2:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
The crude crystals (17.1 g) of di-tert-butyl 2,2- bis[(4-pyridyl)methyl]malonate synthesized by the above process were dissolved in trifluoroacetic acid (90 ml), and the solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resultant concentrated residue was heated for 20 minutes in a bath controlled at 200° C. and then dissolved in methanol (170 ml). A 4N hydrogen chloride in ethyl acetate (100 ml; 400 mmol) was added to the solution, and the mixture was stirred for 2 hours and then concentrated under reduced pressure. The resultant concentrated residue was made basic by addition of aqueous 2.5N sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 6.0 g (yield: 51%) of methyl 2,2-bis[(4-pyridyl)methyl]acetate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[S:7][C:8]([C:10](O)([CH2:13][CH3:14])[CH2:11][CH3:12])=[CH:9][C:5]=2[CH:4]=1.[C:18]1([CH3:25])[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>>[CH2:11]([C:10]([C:20]1[CH:21]=[CH:22][C:23]([OH:24])=[C:18]([CH3:25])[CH:19]=1)([C:8]1[S:7][C:6]2[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:9]=1)[CH2:13][CH3:14])[CH3:12]
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1cc2cc(OC)ccc2s1
Agent: FB(F)F
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(OC)ccc2s1
Yield: 77.9 %

Procedure:
3-(5-Methoxy-benzo[b]thiophen-2-yl)-pentan-3-ol (2.16 g, 8.63 mmol), o-cresol (4.66 g, 43.1 mmol), and BF3-Et2O (1.64 mL, 12.9 mmol) are reacted analogous to Example 1C to afford the title compound (2.29 g, 78%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([NH:15][NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[CH3:25])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:43][C:17]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=3[CH3:25])=[N:16][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(Br)ccc1C(=O)NNC(=O)c1ccc(OC(C)C)c(C#N)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1cc(Br)ccc1-c1nnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 125 °C

Procedure:
In an oven-dried high-pressure tube, 240 mg (0.58 mmol) of N′-(3-cyano-4-isopropyloxyphenylcarbonyl)-4-bromo-2-methylbenzhydrazide (from Step A) was combined with 40 mL of anhydrous toluene, 300 mg of Lawesson's Reagent (0.74 mmol), and 100 μL of pyridine. The tube was sealed with a plastic/teflon cap and the reaction mixture was heated to 125° C. for 2 h. The resulting mixture was cooled down to rt, solvents were removed under reduced pressure and residual solids were dissolved in 10 mL of pyridine. To this mixture, 0.5 g of phosphorous pentasulfide was added and the mixture heated to 110° C. The reaction mixture was combined with ice-water and extracted 2×100 mL of EtOAc. Combined organic layers were dried over sodium sulfate, and solvents removed under reduced pressure. Pure title compound was isolated by flash chromatography using Biotage 40S (eluant: hexanes/EtOAc-4/1) to yield 239 mg: 1H NMR (500 MHZ, CDCl3) δ 1.49 (d, J=6.5, 6H), 2.65 (s, 3H), 4.79 (sep, J=6.5, 1H), 7.13 (dd, J=9.0, 2.0, 1H), 7.50 (dd, J=9.0, 2.0, 1H), 7.56 (d, J=2.0, 1H), 7.63 (d, J=8.0, 1H), 8.17 (d, J=2.0, 1H), 8.24 (dd, J=8.0, 2.0, 1H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:27]=[CH:26][CH:25]=2)O1.O.CCOC(C)=O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:34][Si:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:28]1[C:24]([C:2]2[CH:15]=[CH:14][C:5]([O:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:25][CH:26]=[N:27]1
Reactant: Oc1ccc(Oc2ccc(Br)cc2)cc1
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(4-Bromo-phenoxy)-phenol (7.0 g, 26 mmol), and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (9.4 g, 39 mmol) in a mixture of DME (120 mL) and 2N aqueous Na2CO3 (33 mL) is sparged with Argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (1.5 g, 1.3 mmol) is added to the mixture, and the mixture is heated to 100° C. After 16 hours, the mixture is cooled to room temperature and poured into water/EtOAc. The organic layer is collected, and the aqueous layer is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified on SiO2 (EtOAc/heptanes) to provide Intermediate A.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[C:7](Cl)[N:6]=1)=[O:4].C(O)=O.C(N(CC)CC)C>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ncc(N)nc1N
Temperature: 125 °C
Reaction time: 12 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid methyl ester (8.00 g, 39.5 mmol) in tetrahydrofuran (150 mL) were added tetrakis(triphenylphosphine)palladium(0) (2.28 g, 1.98 mmol), formic acid (2.24 mL, 59.3 mmol) and triethylamine (16.5 mL, 119 mmol) at 0° C. under nitrogen atmosphere, then, the solution was stirred at 125° C. for 12 hours. The reaction solution was cooled to room temperature, and a solid precipitated. This solid was collected by filtration, and the title compound (10.7 g, quantitatively) was obtained as a crude product of a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>COCCO>[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC#N
Reactant: Cc1ccc(CN)cc1
Solvent: COCCO
Product: Cc1ccc(CNC(=O)CC#N)cc1

Procedure:
A solution of 93 g. (0.825 mole) of ethyl cyanoacetate and 100 g. (0.825 mole) of 4-methylbenzylamine in 150 ml. of 2-methoxyethanol is refluxed for 2 hr. After cooling the solid product is isolated by vacuum filtration, washed with pentane and dried to give 90 g. (57.6%) of amide as a white solid: m.p. 124°-6° C.;ν3220 (NH), 2230 (CN), and 1630 cm.-1 (C= O)δ8.77 broad, 1H, NH); 7.17 (s, 4H, phenyl protons), 4.28 (d, 2H, benzyl methylene), 3.67 (s, 2H, CH2CO), and 2.28 (s, 3H, CH3).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:25]([C:27]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:28])[N:26]=1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.28 min; [M+H]+=495.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[C:15]1(O)[CH:22]2[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:24][CH:16]1[CH2:17]3)[CH2:21]2)[C:5]([O:7]C(C)(C)C)=[O:6].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:16]12[CH2:24][CH:20]3[CH2:19][CH:18]([CH2:23][CH:22]([CH2:21]3)[CH:15]1[C:14]1[CH:13]=[CH:12][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[Cl:1])[CH2:17]2
Reactant: CC(C)(C)OC(=O)c1ccc(C2(O)C3CC4CC(C3)CC2C4)c(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(C2C3CC4CC(C3)CC2C4)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
To a solution of tert-butyl 3-chloro-4-(2-hydroxyadamantan-2-yl)benzoate (0.581 g, 1.60 mmol) in dichloromethane (50 mL) was added triethylsilane (5 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at ambient temperature for 20 hours and the reaction solution was concentrated in vacuo to dryness. The residue was triturated with hexanes (15 mL) to afford the title compound (0.27 g, 57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=1.6 Hz, 1H), 7.94 (dd, J=1.6, 8.2 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 3.33 (s, 1H), 2.33 (br s, 2H), 1.98-1.92 (m, 8H), 1.78 (s, 2H), 1.70-1.66 (m, 2H) (OH not observed); MS (ES−) m/z 289.3, 291.3 (M−1).
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:10]=[C:11]([CH3:18])[C:12]4[N:13]([CH:15]=[N:16][N:17]=4)[N:14]=3)[CH2:5][CH2:4]2)[O:2]1>C(O)(=O)C>[CH3:18][C:11]1[C:12]2[N:13]([CH:15]=[N:16][N:17]=2)[N:14]=[C:9]([N:6]2[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]2)[CH:10]=1
Reactant: Cc1cc(N2CCC3(CC2)OCCO3)nn2cnnc12
Solvent: CC(=O)O
Product: Cc1cc(N2CCC(=O)CC2)nn2cnnc12

Procedure:
A solution of 62.5 g of 6-(4,4-ethylenedioxy-1-piperidinyl)-8-methyl-1,2,4-triazolo [4,3-b]pyridazine in 350 ml of aqueous 10% acetic acid was refluxed for 7 hours. The solvent was then evaporated under reduced pressure and the residue was taken up in 1100 ml of boiling ethanol. The ethanol solution was concentrated to 600 ml and cooled in an ice bath. The crystalline solid which formed was separated by filtration, washed with fresh ethanol and then with ethyl ether and dried to give 1-(8-methyl-1,2,4-triazolo [4,3-b]pyridazin-6-yl)-4-piperidinone as cream-colored needles melting at about 196.5°-199° C.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[NH2:11][CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1>CCCCO>[Cl:9][C:6]1[N:5]=[C:4]([NH2:10])[N:3]=[C:2]([NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=2)[C:7]=1[NH2:8]
Reactant: COc1c(C)cnc(CN)c1C
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Solvent: CCCCO
Product: COc1c(C)cnc(CNc2nc(N)nc(Cl)c2N)c1C

Procedure:
A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and 2-aminomethyl-4-methoxy-3,5-dimethyl-pyridine was heated to reflux in n-BuOH for 3 h, following the general procedure 1. HPLC RT was 3.597 min. 1HNMR (CDCl3) δ 8.22 (s, 1H), 7.12 (br. t, 1H), 4.61 (s, 2H), 4.56–4.55 (d, 2H), 3.80 (s, 3H), 3.00 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1>>[CH3:10][O:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)=[CH:4][CH:5]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: COc1ccc(CBr)cn1
Product: COc1ccc(CSc2nc(C)cc(O)n2)cn1
Yield: 75 %

Procedure:
The title compound was prepared by following the procedure described for Example 55 using 6-methoxypyridine-3-carbaldehyde to provide (6-methoxypyridin-3-yl)methanol, which was converted to 5-(bromomethyl)-2-methoxypyridine. The reaction of 5-(bromomethyl)-2-methoxypyridine and 6-methyl-2-sulfanylpyrimidin-4-ol provided 2-{[(6-methoxypyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.975 g, 75% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 3.79 (s, 3H), 4.29 (s, 2H), 5.99 (bs, 1H), 6.74 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 8.19 (s, 1H); M+263.87.