Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[C:18]2[O:17][C:16](=[O:19])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[CH3:20][CH:21]([N:23]1[C:27]([C:28]([NH:30][C:31]2[C:32]3[C:36]([CH:37]=[C:38](B4OC(C)(C)CC(C)(C)O4)[CH:39]=2)=[N:35][N:34](C2CCCCO2)[CH:33]=3)=[O:29])=[CH:26][CH:25]=[N:24]1)[CH3:22].O>O1CCOCC1.CO>[CH3:22][CH:21]([N:23]1[C:27]([C:28]([NH:30][C:31]2[CH:39]=[C:38]([C:10]3[C:18]4[O:17][C:16](=[O:19])[NH:15][C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)=[O:29])=[CH:26][CH:25]=[N:24]1)[CH3:20]
Reactant: O=c1[nH]c2cccc(Br)c2o1
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cccc3[nH]c(=O)oc23)cc2[nH]ncc12
Temperature: 120 °C

Procedure:
A microwave vial was charged with Solvias catalyst (8 mg), tripotassium phosphate (90 mg) and 7-bromo-1,3-benzoxazol-2(3H)-one (from prep. such as US2006/0122189A1, 33 mg). 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (70 mg) in 1,4-dioxane (0.5 ml) was added followed by water (0.1 ml). The reaction was heated under microwave irradiation at 120° C. for 10 min. The reaction was passed through a silica cartridge preconditioned with methanol, washing with methanol, then dried under a stream of nitrogen. The residue was subjected to a DCM/water wash and then dried under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). Appropriate fractions were evaporated under a stream of nitrogen. The residues were dissolved in a minimum amount of methanol and combined. A few drops of 2M HCl (aq) were added and the reaction was left to stand at room temperature. The reaction was then evaporated under a stream of nitrogen, passed through an aminopropyl cartridge and dried to give title compound, 10 mg.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].C1(C)C=CC(S(O[CH2:21][CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH3:23])(=O)=O)=CC=1>C(O)C>[CH2:25]([O:24][CH:22]([CH3:21])[CH2:23][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOC(C)COc1ccc(O)cc1
Reaction time: 2.5 h

Procedure:
11.1 g of hydroquinone, 3.1 g of 85% KOH and 100 ml of ethanol were mixed and the reaction was carried out for 2.5 hours. 10.7 g of (2'-dodecyloxypropyl) p-toluenesulfonate was added dropwise and after the reaction was carried out at 60° C. for 3 hours and by heating under reflux for 7.0 hours, ethanol was evaporated. The residue was diluted with 200 ml of water, acidified with a small amount of hydrochloric acid and then extracted with 500 ml of hexane, followed by recrystallization. Yield: 1.1 g (12%). Optical rotation [α]D26° =-8.6°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([NH2:21])=[N:18][C:19]=2[NH2:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.O>N1C=CC=CC=1>[C:22]1(=[O:27])[N:21]([C:17]2[N:18]=[C:19]([NH2:20])[C:14]([CH2:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:15][N:16]=2)[C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(Cc2cnc(N3C(=O)c4ccccc4C3=O)nc2N)cc(OC)c1OC
Reaction time: 2 h
Yield: 55.6 %

Procedure:
8.7 g of trimethoprim are dissolved in 50 ml of pyridine at about 50° C., and then 4.5 g of phthalic anhydride are added. The mixture is stirred for another two hours at from 80° to 90° C.; after cooling, 100 ml of water are added. The precipitate is washed with water and recrystallized from ethanol. 7 g of 2-phthalimido-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidine of melting point 221° C. are obtained as intermediate product.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:12]3[C:13]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].O1CCOCC1.[Li+].[OH-].Cl>CO>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([S:28][C:11]2[C:12]3[C:13]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18]([CH3:21])(=[O:19])=[O:20])[C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:30][CH:31]=1
Reactant: COc1cc(S(C)(=O)=O)c2c(Sc3ccc(Cl)cc3)c3n(c2c1S(C)(=O)=O)CCC3C(C)C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(S(C)(=O)=O)c2c(Sc3ccc(Cl)cc3)c3n(c2c1S(C)(=O)=O)CCC3CC(=O)O

Procedure:
The compound of Step 1 was dissolved in MeOH (2 mL) and 1,4-dioxane (2 mL) and treated with 1N LiOH for 2 h at room temperature. Addition of 1N NaH2PO4 (3 mL) and 1N HCl (0.4 mL) led to a suspension that was filtered through paper. The solid was air dried overnight yielding 14 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19].[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[C:30](Br)[CH:29]=[N:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[C:30]([NH:1][C:2]2[CH:22]=[CH:21][CH:20]=[C:4]([CH2:5][O:6][C:7]3[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=3[CH2:17][CH2:18][CH3:19])[CH:3]=2)[CH:29]=[N:28][CH:27]=1
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Reactant: COC(=O)c1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCc1c(OCc2cccc(Nc3cncc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
Combine 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (500 mg, 1.67 mmol), 5-bromo-nicotinic acid methyl ester (328 mg, 1.52 mmol) and cesium carbonate (693 mg, 2.13 mmol) in toluene (25 mL) and stir. Purge reaction vessel with Argon. Add BINAP [rac-2,2′-Bis(diphenyl-phosphino)-1,1′-binaphthyl] (142 mg, 0.228 mmol), and palladium acetate (34 mg, 0.152 mmol). Purge reaction vessel with argon. Heat to 100° C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to yield a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to yield a yellow solid (250 mg, 38%):1H NMR (DMSO-d6) δ 0.81 (t, 3H), 1.46 (sextet, 2H), 2.57 (m, 5H), 3.86 (s, 3H), 5.25 (s, 2H), 6.72 (d, 1H), 7.03 (d, 1H), 7.08 (d, 1H), 7.24 (bs, 1H), 7.35 (t, 1H), 8.54 (dd, 1H), 8.69 (bs, 1H), 12.84 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].Cl>CN(C=O)C>[CH2:29]([N:30]([CH2:33][CH3:34])[CH2:31][CH2:32][N:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11]1)[CH3:28]
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: CCN(CC)CCBr
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCN(CC)CC)cc(-c2ccc(F)cc2)c1=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 23.9 %

Procedure:
Ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (270 mg) was suspended in DMF (3.0 ml). Cesium carbonate (1180 mg) and 2-bromo-N,N-diethylethylamine hydrobromide (405 mg) were added sequentially, and the mixture was stirred at 50° C. for six hours. A 1 N aqueous hydrochloric acid solution was added under ice cooling, and the insoluble matter was then removed by filtration through celite. After extraction with ethyl acetate, the organic layer was washed with water and brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->60:1 (v/v)] to give 89 mg of the title compound as an oily substance.
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[C:13]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>CO.O1CCCC1.O>[CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[C:13]3[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Reaction time: 20 h
Yield: 87.6 %

Procedure:
A stirred solution of methyl 4-[5-(cyclo-pentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoate (0.25 g.) in methanol (5 ml.) and tetrahydrofuran (4 ml.), under an atmosphere of nitrogen, was treated with a solution of lithium hydroxide monohydrate (0.12 g.) in water (2 ml.). The mixture was stirred for 20 hours and then concentrated to remove tetrahydrofuran. The resulting aqueous solution was acidified with 1M hydrochloric acid (20 ml.). The white precipitate which formed was separated by filtration, washed with a little water, and recrystallized from a mixture of toluene and hexane to give the title compound (0.212 g., 88%) as an off-white powder: m.p. 157°-158° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=O)[C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][C:17]=2[O:25][CH3:26])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCOCC1>[NH2:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([O:25][CH3:26])[C:16]=1[CH2:15][NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: COc1cccc([N+](=O)[O-])c1C(=O)NC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cccc(N)c1CNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
Into a flame dried flask, N-(1-benzyl-piperidin-4-yl)-2-methoxy-6-nitro-benzamide (1.0 g, 2.8 mmol) and lithium aluminium hydride (0.31 g, 8.45 mmol) were combined. To the mixture was added anhydrous 1,4-dioxane (15 mL). The mixture was slowly brought to reflux over 1 h and stirred at reflux for 16 h. The reaction mixture was cooled to 0° C. and excess lithium aluminium hydride destroyed by dropwise addition of methanol, followed by careful addition of 20% potassium hydroxide. The aluminum salts were filtered, the filtrate concentrated and used as is for the next reaction.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]1([C:14]#[C:15][C:16]2[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=2)[C:21]([OH:23])=[O:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)C>CO>[CH3:1][O:22][C:21](=[O:23])[C:20]1[CH:24]=[C:16]([C:15]#[C:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:17]=[N:18][CH:19]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Add trimethylsilyl diazomethane (2.25 g, 19.7 mmol) to a cooled suspension of 5-phenylethynyl-nicotinic acid (2.0 g, 8.9 mmol) in 4:1 diethyl ether: methanol (30 mL) at 0° C. Warm to room temperature, stir for 2 h and concentrate. Purify the residue by silica gel chromatography, eluting with 0:100 to 50:50 ethyl acetate:hexanes, to give the title compound as a white solid (1.8 g, 85%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][NH:9][C:10]([C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:24])=[O:11])[CH2:2]1.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[C:31](OB(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[S:16][C:12]([C:10]([NH:9][CH2:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][N:1]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]([O:26][CH3:25])=[O:28])[CH2:2]3)=[O:11])=[C:13]([CH3:24])[N:14]=2)=[CH:18][CH:19]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCCC(CNC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 46 %

Procedure:
Using N-(perhydroazepin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (200 mg, 0.550 mmol) and 3-(methoxycarbonyl)phenylboric acid (198 mg, 1.10 mmol), the same procedure was followed as in Example 2 to give 126 mg (46%) of the desired compound as a colorless powder.
Reaction SMILES: [CH:1]1([C:4]([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][C:10]=3[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:8]=2)=[N:5][OH:6])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:39][CH2:40][O:41][CH3:42].O>O1CCCC1>[CH3:42][O:41][CH2:40][CH2:39][O:6][N:5]=[C:4]([CH:1]1[CH2:2][CH2:3]1)[C:7]1[C:15]2[CH:14]=[CH:13][C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][C:10]=2[N:9]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:8]=1
Reactant: C[Si](C)(C)CCOCn1nc(C(=NO)C2CC2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCON=C(c1nn(COCC[Si](C)(C)C)c2c1C=CC(c1ccccc1)(c1ccccc1)C2)C1CC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 0.35 g of the E isomer of cyclopropyl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone oxime in 10 cm3 of tetrahydrofuran is added dropwise to a suspension of 0.036 g of sodium hydride (at 60% in oil) in 7 cm3 of tetrahydrofuran. After stirring the reaction mixture for about 2 hours in the region of 20° C., a solution of 0.16 g of 1-bromo-2-methoxyethane in 5 cm3 of tetrahydrofuran is poured into the solution obtained. After stirring in the region of 20° C. for about two and a half hours, 5 cm3 of water are added and the solution is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 20 cm3 of water and extracted with three times 40 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated. After flash chromatography on a column of silica [eluent: dichloromethane/ethyl acetate (99/1 by volume)], 0.32 g of the E isomer of cyclopropyl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone O-(2-methoxyethyl)oxime is thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][CH:15]=2)[CH:12]=1.[I:16]I>O.CCO>[F:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][C:15]=2[I:16])[CH:12]=1
Reactant: II
Reactant: Fc1ccc2cncn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccc2c(I)ncn2c1

Procedure:
To a solution of sodium bicarbonate (1.3 g, 15.4 mmol) in water (3.66 mL) was added 6-fluoroimidazo[1,5-a]pyridine (see Example 32, 560 mg, 4.11 mmol) in EtOH (7.31 mL) followed by iodine (1.46 g, 5.76 mmol) at room temperature. After 16 h another 800 mg of iodine was added. After a further 16 h the reaction mixture was quenched with sodium thiosulfate and diluted with ethyl acetate. The organic phase was washed with water and brine then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, ethyl acetate/hexane gradient). The product contained minor impurities and was used without further purification. MS (M+H)+=262.9; 1H NMR (CDCl3) δ: 8.14 (s, 1H), 7.90 (m, 1H), 7.35 (m, 1H), 6.77 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.[CH3:16][O-:17].[Na+].CO.O.Cl>CO>[CH3:16][O:17][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: C[O-]
Reactant: COC(=O)c1ccc(CCl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCc1ccc(C(=O)O)c([N+](=O)[O-])c1

Procedure:
A mixture of methyl 4-chloromethyl-2-nitrobenzoate (1.6 g), 28% sodium methoxide-methanol solution (2.5 ml) in methanol (16 ml) was stirred under reflux for 24 hours. To this mixture, water (5 ml) was added and the mixture was stirred for 2 hours, acidified with 1N hydrochloric acid, extracted with ethyl acetate. The combined organic extract was washed with water, dried over magnesium sulfate and evaporated to give 4-methoxymethyl-2-nitrobenzoic acid (0.84 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(c2ccc(N)cn2)CC1

Procedure:
A mixture of intermediate (1) (0.0102 mol) in THF (50 ml) was hydrogenated with palladium on carbon (10%; 0.3 g) as a catalyst for 30 minutes at a temperature of 50° C. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding (5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester (intermediate 2).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2O[C:16](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:17][N:18]=2)=[CH:9][CH:8]=1>C(O)(=O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[NH:5][C:16](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:17][N:18]=2)=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(Nc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 150 °C
Reaction time: 12 h
Yield: 53.9 %

Procedure:
Acetic acid (10 mL) and ammonium acetate (6.8 g) were added to (4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazol-2-yl}amine (692 mg), and the reaction solution was stirred at 150° C. for 12 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The insoluble matter generated during separation was added to the resulting extract, and THF and ethanol were further added to provide a mixed solution. The mixed solution was concentrated under reduced pressure and solidified with ethyl acetate and diethyl ether to obtain 372 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1Cl.[CH2:13]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:21][NH2:22])[CH2:14][CH2:15][CH3:16].O1CCOCC1>O>[Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[CH:19]=1
Reactant: CCCCOc1cc(CN)ccc1OC
Reactant: CCOc1n[nH]c(=O)c(Cl)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: CCCCOc1cc(CNc2c(OCC)n[nH]c(=O)c2Cl)ccc1OC
Reaction time: 15 h

Procedure:
A mixture comprising 7.32 g of 4,5-dichIoro-6-ethoxy-3(2H)pyridazinone prepared in Reference Example 2, 21.95 g of 3-n-butoxy-4-methoxybenzylamine, 60 ml of 1,4-dioxane and 60 ml of water, was refluxed under stirring for 15 hours. Then, most 1,4-dioxane was distilled off under reduced pressure, and dilute hydrochloric acid was added for acidification. Then, chloroform was added thereto, and the mixture was vigorously shaked. The precipitated crystals were separated by filtration, and the chloroform layer of the filtrate was subjected to liquid separation and washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light yellow oily substance. The product was crystallized from n-propanol-di-i-propyl ether (1:9 v/v), to obtain 10.48 g of the above identified compound having a melting point of from 117° to 118° C. as colorless crystals.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][OH:10])([CH3:3])[CH3:2].[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15](O)=[CH:14][C:13]=2[O:12]1.C1(N=C=NC2CCCCC2)CCCCC1>CCOCC>[CH:1]([O:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][O:10][C:16]1[CH:15]=[CH:14][C:13]2[O:12][CH2:11][O:19][C:18]=2[CH:17]=1)([CH3:3])[CH3:2]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(C)OCCC=CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: CC(C)OCCC=CCOc1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
A mixture of 7.2 g (0.05 mol) of 5-isopropoxy-2-penten-1-ol, 6.9 g (0.05 mol) of 3,4-methylendioxy-phenol, and 10.3 g (0.05 mol) of dicyclohexyl-carbodiimide is stirred at 105° for 16 hours. After cooling 50 cc of ether are added, the mixture is filtered and the filtrate is evaporated. The residue is chromatographed on silica gel with hexane/ethyl acetate 9:1 and 5-(5-isopropoxy-2-pentenyloxy)-1,3-benzodioxol is obtained as colourless oil which is identical with the product produced in accordance with Example 39.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH3:27])[CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:19]([CH3:18])[CH:20]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: Cc1ccc(CN)cc1C
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-n3cccn3)c2C#N)cc1C

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile and 3,4-dimethylbenzylamine in DME. ES-MS m/e (%): 320 (M+H+, 100).