Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), phenylboronic acid (121 mg), and tetrakistriphenylphosphine palladium (23 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (0.5 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (74 mg, yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=O)=[C:11]([CH:16]=2)[C:12](OC)=[O:13])=[CH:4][C:3]=1[O:23][CH3:24].[NH2:25][C@@H:26]1[C@@H:31]([OH:32])[CH2:30][CH2:29][O:28][CH2:27]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[CH:16]=[C:11]3[C:10]([CH2:17][N:25]([C@@H:26]4[C@@H:31]([OH:32])[CH2:30][CH2:29][O:28][CH2:27]4)[C:12]3=[O:13])=[C:9]([CH3:19])[C:8]=2[CH3:20])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COC(=O)c1cc(Cc2ccc(F)c(OC)c2)c(C)c(C)c1C=O
Reactant: N[C@H]1COCC[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1cc(Cc2cc3c(c(C)c2C)CN([C@H]2COCC[C@@H]2O)C3=O)ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.8 %

Procedure:
To a solution of methyl 5-(4-fluoro-3-methoxybenzyl)-2-formyl-3,4-dimethylbenzoate (0.35 g) in THF (4.00 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.12 g) and anhydrous magnesium sulfate (0.26 g), and the mixture was stirred at room temperature for 5 hr under nitrogen atmosphere. The insoluble substance was removed by filtration, the filtrate was concentrated, and the residue was diluted with methanol (2.00 mL)-THF (4.00 mL). Sodium triacetoxyborohydride (0.45 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.13 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH:13]=[CH:14][C:15]([O:17]C)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[CH:37][CH:36]=2)=[O:34])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29]1[CH:48]=[CH:47][C:32]([C:33]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[CH:39][CH:40]=2)([OH:34])[CH:13]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:15][OH:17])=[CH:31][CH:30]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C=Cc1ccc(OCc2ccccc2)cc1
Reactant: CN(C)CCOc1ccc(C(=O)c2ccc(OCc3ccccc3)cc2)cc1
Product: CN(C)CCOc1ccc(C(O)(c2ccc(OCc3ccccc3)cc2)C(CCO)c2ccc(OCc3ccccc3)cc2)cc1
Yield: 64 %

Procedure:
1,2-bis (4-benzyloxyphenyl)-1-[4-[2-(N,N-dimethylamino) -ethoxy]phenyl]butan-1,4-diol is prepared according to the procedure described in Example 2 using methyl 4-benzyloxy-cinnamate and 4-benzyloxy-4'-dimethylaminoethoxybenzophenone as starting materials. The product is recrystallized from toluene. Yield is 64%.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7](CO)(COC(=O)C=C)COC(=O)C=C)(=[O:4])[CH:2]=[CH2:3].O=C=[N:24]C1CC(C)(C)CC(C)(CN=C=O)C1>CC(CC(C)=O)C>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[NH2:24][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: C=CC(=O)OCC(CO)(COC(=O)C=C)COC(=O)C=C
Solvent: CC(=O)CC(C)C
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 4 h
Yield: 499.5 %

Procedure:
A solution containing 50 ml of MIBK and 59.6 g (0.20 moles) of pentaerythritol triacrylate was added dropwisely to a solution containing 100 ml of MIBK and 22.2 g (0.1 moles) of isophorone diisocyanate included in a 500 ml flask at the temperature of 25° C., while air bubbling was conducted. After the dropwise addition was completed, 0.3 g of dibutyltin dilaurate was added to the mixture, and heating and stirring were conducted for 4 hours at the temperature of 70° C. After the reaction was completed, the obtained reaction solution was washed with 100 ml of 5% hydrochloric acid. Then, an organic layer was separated, and then solvent was removed under reduced pressure at the temperature of 40° C., or less to obtain 80.5 g of urethane acrylate which was a transparent and colorless viscous liquid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[C:19]3[N:18]4[CH:20]=[CH:21][CH:22]=[C:17]4[C:16](=O)[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:2]=1.[ClH:24].[NH2:25][OH:26]>N1C=CC=CC=1>[ClH:24].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[C:19]3[N:18]4[CH:20]=[CH:21][CH:22]=[C:17]4[C:16](=[N:25][OH:26])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:2]=1
Reactant: O=C1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Yield: 102.2 %

Procedure:
In a 100 ml round-bottomed flask, a mixture of 231 mg of 5-quinolin-3-ylpyrrolo[1,2-a]indol-9-one obtained according to the preceding stage and 164 mg of hydroxylamine hydrochloride in 20 ml of pyridine is refluxed under argon. After heating for 1.5 hours, the reaction medium is evaporated to dryness under vacuum. The residue is taken up in a saturated solution of sodium bicarbonate and extracted twice with ethyl acetate. The combined organic phases are washed with a saturated solution of sodium bicarbonate and then a saturated solution of sodium chloride, dried over magnesium sulphate, and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (2% to 3% v/v) in dichloromethane. 277 mg of 5-quinolin-3-ylpyrrolo[1,2-a]indol-9-one oxime hydrochloride are obtained in the form of a yellowish solid, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][NH2:13].[C:14](=[O:17])([O-])[O-:15].[Na+].[Na+]>CO.O>[NH:12]([C:14]([O:15][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:17])[NH:13][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NN
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NNC(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 0.75 h
Yield: 71.9 %

Procedure:
Benzyl chloroformate (19.73 mL, 140 mmol) was added dropwise to a solution of hydrazine (2 mL, 63.7 mmol) in methanol (200 mL). Approximately half way through the addition, dropwise addition of a solution of sodium carbonate (14.86 g, 140 mmol) in water (150 mL) commenced. The resulting slurry was stirred for about 45 min before being filtered under suction, isolating a solid which was washed with ice water. The resulting filtrate was concentrated to remove the methanol, yielding a small quantity of solid material upon filtration. This solid material was again washed with ice water. The combined solids were recrystallized from straight toluene. The resulting white solid was dried in a vacuum oven at 60° C. for 5 hours. This yielded bis(phenylmethyl) 1,2-hydrazinedicarboxylate (13.74 g, 45.8 mmol, 71.8% yield) as a white crystalline solid.
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2c(c3ccccc3n2-c2ccccc2)C1
Temperature: 120 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A mixture of 1,1-diphenylhydrazine hydrochloride (0.365 g, 1.65 mmol) and 4-oxo-1-piperidinecarboxylic acid tert-butyl ester (0.329 g, 1.65 mmol) in pyridine (3 mL) was heated in a sealed tube at 120° C. with stirring for 3 h. The reaction mixture was subsequently cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed (SiO2/hexanes:ethyl acetate, 3:2) to give the title compound (0.214 g, 37%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.51 (m, 2H), 7.40 (m, 1H), 7.35 (m, 2H), 7.26 (m, 2H), 7.14 (m, 2H), 4.72 (s, 2H), 3.78 (s, 2H), 2.71 (s, 2H), 1.51 (s, 9H); LCMS: m/e 349 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([S:35]([N:34]([CH3:39])[CH3:33])(=[O:37])=[O:36])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 102 %

Procedure:
To a suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.17 mmol) in toluene (1 mL) was added N,N-dimethylsulfamoyl chloride (27 mg, 0.19 mmol) and triethylamine (73 μL, 0.52 mmol). The reaction was stirred at rt for 17 h. Additional N,N-dimethylsulfamoyl chloride (27 mg, 0.19 mmol) and triethylamine (73 μL, 0.52 mmol) were added and the reaction continued to stir at rt for 6 h. The mixture was partitioned between EtOAc (20 mL) and H2O (20 mL). The layers were separated and the organic phase was washed with saturated, aqueous NaHCO3 (20 mL), brine, dried (Na2SO4) and concentrated. The resulting solid was triturated with Et2O and was collected by vacuum filtration to afford 92 mg (99%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1 H), 7.90 (s, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.28-7.37 (m, 5 H), 7.14 (d, 1 H), 6.63 (s, 1 H), 5.65 (s, 2 H), 3.67 (d, 2 H), 3.22-3.33 (m, 1 H), 3.01 (t, 2 H), 2.77 (s, 6 H), 2.07 (d, 2 H), 1.62-1.77 (m, 2 H); ES-MS m/z 531.26 [M+H]+, HPLC RT (min) 2.75.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9](=[O:21])[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:23]([O-])([O-:25])=[O:24].[Na+]>S(=O)(=O)(O)O>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:18])([F:19])[F:20])=[C:14]([N+:23]([O-:25])=[O:24])[CH:15]=3)[NH:10][C:9](=[O:21])[C:8]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n(C2CCCCC2)c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 20 g (64 mmol) of 1-cyclohexyl-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione in 400 ml of concentrated sulfuric acid was cooled to 0° C., 5.4 g (64 mmol) of sodium nitrate were added a little at a time over the course of one hour, and the mixture was stirred at room temperature for 3 hours. It was then poured into ice-water, and the crude product was filtered off with suction and recrystallized from methanol.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH:40]=[N:39][C:38]2=[O:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:35]5[CH:36]=[C:37]6[C:42](=[CH:43][CH:44]=5)[NH:41][CH:40]=[N:39][C:38]6=[O:45])=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=c1nc[nH]c2ccc(Br)cc12
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4[nH]cnc(=O)c4c3)cc2F)C1
Temperature: 25 °C
Yield: 11 %

Procedure:
A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.238 mmol) in 1,4-dioxane (1.5 mL) was treated with 6-bromo-4(1H)-quinazolinone (0.238 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)-dichloromethane adduct (10 mg) and 2M aq potassium carbonate (0.715 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over sodium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions from the HPLC were combined, adjusted to pH˜5 with the addition of saturated aq sodium bicarbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting product was then purified by flash chromatography (0-10% methanol/dichloromethane). The resulting product was suspended in water (0.5 mL) and was lyophilized to afford the title compound as an amorphous white solid (11%). MS(ES)+ m/e 475.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:26][CH:27]=2)[N:13]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.16 ml of 4-trifluoromethoxy-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. The solvent is evaporated off, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 129 mg of expected product is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]([O:27][CH2:28][CH3:29])=[CH2:26])CCC>CN1C(=O)CCC1.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>[CH2:28]([O:27][C:25]([C:2]1[N:7]=[CH:6][C:5]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1)=[CH2:26])[CH3:29]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(Cn2cnc3cc(Cl)ncc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C=C(OCC)c1cc2ncn(Cc3ccc(OC)cc3)c2cn1
Temperature: 140 °C
Yield: 77.7 %

Procedure:
A mixture of 6-chloro-3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridine (500 mg, 1.83 mmol), tributyl(1-ethoxyvinyl)stannane (866 mg, 2.40 mmol), Pd (PPh3)4 (243 mg, 0.27 mmol) in NMP (10 mL) was heated at 140° C. for 72 h. The reaction mixture was quenched with water and extracted with EtOAc (50 mL×3). The combined extracts were washed with water (100 mL) and brine (50 mL), dried (MgSO4) filtered and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with 3% MeOH/DCM to afford 440 mg (78%) of 6-(1-ethoxyvinyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridine as a gray solid. MS (EST): m/z=310.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C:7]2[C:18]3[C:17](=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=3)[NH:20][C:8]=2[CH3:9])=[CH:4][CH:3]=1
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)COc1ccc(Cl)cc1
Solvent: CCO
Product: Cc1[nH]c2ccc(F)cc2c1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Chloro-phenoxy)-propan-2-one (2.05 g) was added to a stirred solution of (4-fluoro-phenyl)-hydrazine (1.4 g) in ethanol (30 ml) at RT. After 2 h, the solvent was removed under reduced pressure and the residue dissolved in DCM (30 ml). Phosphorus trichloride (1.06 ml) was added dropwise to the solution and after stirring at RT for 16 h the reaction was quenched with aq. sodium hydrogencarbonate solution. The mixture was extracted with DCM, the organics washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 20% ethylacetate/iso-hexane. Yield 0.75 g
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:16][N:17]1[C:21]2[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=2[C:19]([C:28]([O:30]CC)=O)=[N:18]1>C1COCC1>[CH3:5][O:4][N:3]([CH3:2])[C:28]([C:19]1[C:20]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22](=[O:27])[C:21]=2[N:17]([CH3:16])[N:18]=1)=[O:30]
Reactant: CCOC(=O)c1nn(C)c2c1CCCCC2=O
Reactant: CNOC
Agent: Cl
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nn(C)c2c1CCCCC2=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (650 mg, 0.67 mmol) in 2 mL of anhydrous THF under argon, 1M solution of LiN(TMS)2 in THF (1.32 mL, 1.32 mmol) at 0° C. were added dropwise. The mixture was stirred at 0° C. for 0.5 h then ethyl 1-methyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxylate (50 mg, 0.22 mmol) in 5 mL of anhydrous THF at 0° C. were added dropwise. Ice bath was removed and the mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with AcOEt (2×30 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated to dryness. The crude solid was used without further purification. 52 mg (quantitative yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].N1C=CC=CC=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19].N#N>O.C(Cl)Cl>[C:16]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)Cl
Reactant: O=Cc1cccc(O)c1
Agent: N#N
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Oc1cccc(C=O)c1
Reaction time: 20 h
Yield: 74.9 %

Procedure:
To a 250 mL dry round bottom flask were added 3-hydroxybenzaldehyde (5.0 g, 41.0 mmol), anhydrous CH2Cl2 (50 mL). The solution was cooled in an ice-water bath, then pyridine (6.64 mL, 82.0 mmol) was added. To the resulting solution, butyryl chloride (5.15 mL, 49.2 mmol) was added slowly under stirring and N2. The mixture was first stirred at 0° C. for 2 hours, then at room temperature for 20 hours. To the reaction mixture, water (80 mL) was added and the CH2Cl2 layer was separated. The aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3-formylphenyl butyrate (5.9 g) as colorless oil. Yield: 75%. 1H NMR (CDCl3, 300 MHz): δ=9.96 (s, 1H), 7.72 (t of d, J=1.2, 7.5 Hz, 1H), 7.60 (t, J=2.4 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.36-7.32 (m, 1H), 2.56 (t, J=7.5 Hz, 2H), 1.78 (sextet, J=7.2 Hz, 2H), 1.04 (t, J=7.5 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=191.2, 171.7, 151.3, 137.7, 130.1, 127.8, 127.2, 122.2, 36.0, 18.3, 13.5.
Reaction SMILES: FC(F)(F)C1C=CC([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)=NC=1.Br[C:19]1[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=1.C(OC(=O)N[C@@H]1CCN(C2C(C(F)(F)F)=CC=CN=2)C1)(C)(C)C.FC(F)(F)C1C(N2CC[C@@H](N)C2)=NC=CC=1>>[F:25][C:24]([F:27])([F:26])[C:22]1[N:23]=[C:19]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[S:20][CH:21]=1
Reactant: FC(F)(F)c1csc(Br)n1
Reactant: NC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Agent: N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Product: NC1CCN(c2nc(C(F)(F)F)cs2)CC1

Procedure:
Prepared from D8 and 2-bromo4-trifluoromethylthiazole (J. A. Edwards Ger. Offen., 2252070, 1973) in a manner similar to that described in D1 and D2. The following were prepared using methods described above and in a manner similar to that of D18:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:12]=1[CH3:13])[C:7]([O:9]CC)=[O:8].C(O)C.[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:12]=1[CH3:13])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(OC)ccc(Br)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Br)c(C)c1C(=O)O
Reaction time: 42 h

Procedure:
A mixture of 6A (9.8 g, 34.1 mmol), water (40 ml), ethanol (80 ml) and sodium hydroxide (2.7 g, 68.3 mmol) is heated under reflux with stirring for 42 hours. The reaction mixture is diluted with water (80 ml), acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic phase is separated and concentrated. The solid material is collected by filtration, washed with water and dried yielding off-white crystals, 5.4 g (61%), mp 81-83° C.