Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[C:6]([CH3:14])=[C:5]2[OH:15].[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:17]>>[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH:8]=[C:7]([CH:12]=[O:13])[C:6]=2[CH3:14])=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH3:17]
Reactant: Cc1c(C=O)cc2ccc(F)cc2c1O
Reactant: CCS(=O)(=O)c1ccc(F)cc1
Product: CCS(=O)(=O)c1ccc(Oc2c(C)c(C=O)cc3ccc(F)cc23)cc1

Procedure:
Starting with 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carbaldehyde (115 mg, 0.6 mmol) and 1-ethanesulfonyl-4-fluoro-benzene (226 mg, 1.2 mmol), using a method analogous to the one described for the methyl ester of example 1-1,4-(4-ethanesulfonyl-phenoxy)-6-fluoro-3-methyl-naphthalene-2-carbaldehyde (120 mg, 57%) was obtained as a yellow solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 10.35 (s, 1H), 8.32 (s, 1H), 8.07 (dd, J=8.97, 5.68 Hz, 1H), 7.84 (d, J=9.09 Hz, 2H), 7.33-7.45 (m, 2H), 6.94 (d, J=8.84 Hz, 2H), 3.12 (q, J=7.41 Hz, 2H), 2.59 (s, 3H), 1.31 (t, J=7.45 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][O:5][CH:6]=1.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:7]([O:1][C:2]1[CH:3]=[N:4][O:5][CH:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cnoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(COc2cnoc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture containing 200 mg of 4-hydroxyisoxazole in 10 ml of acetone together with 1.5 equivalents of benzyl bromide and 1.5 equivalents of potassium carbonate is stirred at about 25° C. for five hours. The solid is filtered and the filtrate concentrated to an oil. The crude material is purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[S:15][CH:14]3[C:16](=[O:19])[N:17]([CH3:18])[CH:11]([C:12](=[O:21])[N:13]3[CH3:20])[S:10]2)=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[S:15][CH:14]3[C:16](=[O:19])[N:17]([CH3:18])[C:11]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:12](=[O:21])[N:13]3[CH3:20])[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2SC3C(=O)N(C)C(S2)C(=O)N3C)cc1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2SC3C(=O)N(C)C(Cc4ccccc4)(S2)C(=O)N3C)cc1
Temperature: -78 °C
Reaction time: 0.13 h
Yield: 40.2 %

Procedure:
Thioacetal 5 (194 mg, 0.6 mmol, 1 eq.) was dissolved in anhydrous THF (25 mL) and the solution was cooled to −78° C. To the stirred solution 1.54 M n-butyllithium in hexane (545 μL, 0.84 mmol, 1.4 eq.) was added dropwise over a period of 1 min. After 30 second benzyl bromide (356 μL, 513 mg, 3 mmol, 5 eq) was added to the stirred mixture over a period of 30 sec. After the mixture was stirred for 8 min at −78° C. the resulting red, cloudy solution was allowed to warm to room temperature and was stirred. It took about 30 min. The TLC shows one major product and a little (˜5%) of starting material. Saturated NaCl solution was added into the reaction mixture and the solution was extracted with dichloromethane. The organic solution was washed with water twice, dried under MgSO4 and concentrated under vacuum. The oily residue was treated with hexane. One part of the material got solid and the hexane solution was removed. The yellow solid was washed again with hexane and dried under vacuum. The solid crude material was dissolved in dichloromethane (2 mL), methanol (4 mL) and hexane (about 20 mL) was added. The white precipitate was filtered off to give the pure product 100 mg of 26 (40.8%). 1H NMR (CDCl3, TMS, ppm) δ: 7.36 (d, J=8.7 Hz, 2H), 724 (m, 51), 6.88 (d, J=8.7 Hz, 2H), 5.19 (s, 1H), 5.10 (s, 1H), 4.15 (d, J=16.6 Hz, 1H), 3.82 (s, 3H), 3.25 (d, J=16.5 Hz, 1H), 3.15 (s, 3H), 3.11 (5, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:24]=[CH:23][N:22]=1.C(=O)([O-])O.[Na+]>C(O)C.[Cl-].[Na+].O>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:7][C:6]=4[CH:19]=3)[N:26]=2)[CH2:32][CH2:31]1
Reactant: CN1CCN(c2ccnc(Cl)n2)CC1
Reactant: Nc1ccc2sc(NC(=O)c3ccccc3)nc2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccnc(Nc3ccc4sc(NC(=O)c5ccccc5)nc4c3)n2)CC1

Procedure:
N-{5-[4-(4-Methylpiperazin-1-yl)pyrimidin-2-ylamino]benzothiazol-2-yl}benzamide was prepared by heating a mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 50 mg, 0.186 mmol) and 2-chloro-4-(4-methylpiperazin1-yl)pyrimidine (IM 10, 40 mg, 0.186 mmol) in ethanol (3 mL) to 80° C. for 4 days. Brine (25 mL) and saturated sodium hydrogencarbonate solution (25 mL) were, added and the product was extracted with chloroform (3×40 mL) and ethyl acetate (40 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed. The residue was purified by pTLC (dichloromethane:methanol=4:1) to yield a solid (44 mg, 99 μmol, 53%). LC/ESI-MS: m/z=446 [M+H]+; m/z=444 [M−H]−; Rt=2.38 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:9][CH2:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:5]=[CH:6][CH:7]=1.ClCCl>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C(CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2)c1
Yield: 27.9 %

Procedure:
The acid prepared in Example 38 (8.2 g, 21.6 mmol) was dissolved in methanol (150 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (35% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a residue which was dissolved into dichloromethane and dried over sodium sulphate. The solvent was evaporated in vacuo to give 2.3 g (28%) of the title compound as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[NH:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:17]=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[N:10][CH2:17][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:9])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CS(=N)(=O)c1ccc(Br)cc1
Reactant: C=O
Product: CS(=O)(=NCN1CCCC1)c1ccc(Br)cc1

Procedure:
Following the procedures given for the Mannich reaction in Canadian Patent 1,102,803, the title compound is prepared from S-(4-bromophenyl)-S-methylsulfoximine, pyrrolidine, and 37% formaldehyde solution.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]1=[O:32].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[ClH:17].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:22]4=[O:32])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: O=C1N(CCCCl)CCN1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: Cl
Product: O=C1N(CCCN2CCN(c3cccc4c3OCCO4)CC2)CCN1c1ccccc1

Procedure:
A mixture of 1-(1,4-benzodioxan-5-yl)-piperazine (1.5 g), 1-(3-chloro-1-propyl)-3-phenyl-2-imidazolidinone (1.4 g), potassium carbonate (3 g), and potassium iodide (0.1 g) in methyl isobutyl ketone was refluxed for 20 h. Filtration and removal of solvent in vacuo gave a viscous oil which was separated by column chromatography (silica gel, eluent: ethyl acetate/methanol/triethylamine=15:4:1). The title compound was isolated as an oil which crystallized as the hydrochloride salt from acetone by addition of hydrochloric acid. Yield: 1.9 g, mp: 229-32° C. 1H NMR (δ, DMSO): 1.95-2.15 (m, 2H), 3.00-3.25 (m, 6H), 3.30 (t, 2H), 3.40-3.65 (m, 4H), 3.70-4.00 (m, 4H), 4.15-4.30 (m, 4H), 6.45-6.70 (m, 2H), 6.75 (t, 1H), 7.00 (t, 1H), 7.30 (t, 2H), 7.60 (d, 2H), 11.30 (b, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]1[NH:8][C:7]2[C:2](=[N:3][CH:4]=[N:5][CH:6]=2)[N:1]=1
Reactant: Nc1cncnc1N
Reactant: COc1ccc(C#N)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(-c2nc3ncncc3[nH]2)c(OC)c1
Temperature: 120 °C

Procedure:
A mixture of 2 g of 4,5-diamino-pyrimidine, 4 g of 2,4-dimethoxy-benzonitrile, 6 g of p-toluene sulfonic acid hydrate, and 40 ml of benzene was heated, whereby the benzene was distilled off. The residue was heated for 30 minutes at 120° C. After cooling the residue was triturated with 2 N ammonia and extracted with ethyl acetate. The ethyl acetate phase was extracted with 2 N hydrochloric acid, the aqueous phase was neutralized and again extracted with ethyl acetate, and subsequently the organic phase was extracted with 2 N sodium hydroxide solution. When the aqueous phase was neutralized, the product was precipitated and recrystallized from water.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:27]([CH:24]3[CH2:26][CH2:25]3)=[O:28])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(NC(=O)C2CC2)C(=O)c2ccccc2C1=O
Yield: 103.8 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with cyclopropyl carbonyl chloride (0.07 mL, 0.77 mmol) and triethylamine (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (235 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[NH2:12][CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].[H][H]>C(O)C.S(=O)(=O)(O)O.[Pt]>[CH3:1][C:2]1([CH3:11])[CH2:3][CH:4]([CH:13]([P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[NH2:12])[CH2:6][C:7]([CH3:10])([CH3:9])[NH:8]1
Reactant: [H][H]
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: CCOP(=O)(CN)OCC
Agent: [Pt]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOP(=O)(OCC)C(N)C1CC(C)(C)NC(C)(C)C1

Procedure:
31.0 g (0.21 mol) of triacetonamine and 33.4 g (0.20 mol) of diethyl aminomethylphosphonate are dissolved in 500 ml of ethanol, and the solution is hydrogenated, with the addition of 3 g of platinum-on-charcoal (containing 5% of platinum) and 3 drops of concentrated sulphuric acid, under a slight excess pressure until the absorption of hydrogen has ceased. The catalyst is filtered off and the filtrate is distilled. In this way is obtained diethyl (2,2,6,6-tetramethyl-4-piperidyl)-aminomethylphosphonate as a fine fraction which boils, under a pressure of 0.35 mm Hg, at a temperature of 130°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:5]=2[N:4]=1.[CH3:14][Si:15]([CH3:20])([CH3:19])[C:16]#[C:17][CH3:18]>>[F:13][C:11]1[CH:10]=[CH:9][C:6]2[N:7]([CH3:8])[C:3]([CH2:2][CH2:18][C:17]#[C:16][Si:15]([CH3:20])([CH3:19])[CH3:14])=[N:4][C:5]=2[CH:12]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Cn1c(CCl)nc2cc(F)ccc21
Product: Cn1c(CCC#C[Si](C)(C)C)nc2cc(F)ccc21
Yield: 99.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(D), from of 2-(chloromethyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (270 mg, 1.36 mmol) and trimethyl(prop-1-ynyl)silane (183 mg, 1.63 mmol). The crude residue was used in the next step without any purification. 5-fluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (373 mg, Yield: 100%) as a brown oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([N:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7]2)[CH2:3][CH2:2]1.BrCCCC[C:21]12[CH:31]=[CH:30][CH:29]=[CH:28][CH:22]1[C:23]([NH:25][C:26]2=[O:27])=[O:24]>>[N:1]1([CH2:2][CH2:3][CH2:4][CH2:5][C:28]2[CH:29]=[CH:30][CH:31]=[C:21]3[C:26]([NH:25][C:23](=[O:24])[C:22]=23)=[O:27])[CH2:2][CH2:3][C:4]2([N:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7]2)[CH2:5][CH2:6]1
Reactant: O=C1NC(=O)C2(CCCCBr)C=CC=CC12
Reactant: C1=NC2(CCNCC2)Oc2ccccc21
Product: O=C1NC(=O)c2c(CCCCN3CCC4(CC3)N=Cc3ccccc3O4)cccc21

Procedure:
From spiro[2H- 1,3-benzoxazine-2,4'-piperidine] and 2-(4-bromobutyl)-phthalimide using the procedure described for Example 15, Step 5 there was obtained a white solid: mp 165°-7° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:28]=[CH:27][C:9]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:17]([C:21](Cl)=[O:22])=[N:16][CH:15]=[C:14]([O:24][CH3:25])[C:13]=3[C:12]2=[O:26])=[CH:8][CH:7]=1>O.CC(C)=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:17]([C:21]([N:1]=[N+:2]=[N-:3])=[O:22])=[N:16][CH:15]=[C:14]([O:24][CH3:25])[C:13]=3[C:12]2=[O:26])=[CH:27][CH:28]=1
Reactant: COc1cnc(C(=O)Cl)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cnc(C(=O)N=[N+]=[N-])c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.33 h

Procedure:
To a solution of sodium azide (0.24 g, 3.69 mmol) in water (2.5 mL) was added 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl chloride (1.17 g, 3.36 mmol) in acetone (15 mL). After 20 minutes, the product mixture was concentrated under vacuum to provide 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carbonyl azide. The crude azide (1.19 g, 3.35 mmol) in DMF (20 mL) was heated to 110° C. After 20 minutes, the product mixture was cooled for 10 minutes, then 1N NaOH (3.3 mL) was added. After 20 minutes, the mixture was concentrated under vacuum, re-dissolved in toluene and CHCl3 and evaporated. The residue was partitioned between CHCl3 and saturated sodium bicarbonate. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[N:6]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[CH3:26][O:27][C:28](=[NH:30])[NH2:29]>C(#N)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[N:10]=[C:5]([NH:30][C:28](=[NH:29])[O:27][CH3:26])[N:6]=1
Reactant: COC(=N)N
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: COC(=N)Nc1nc(OC)cc(OC)n1
Reaction time: 17 h
Yield: 171 %

Procedure:
54.5 g (0.25 mol) of 2-methylsulphonyl-4,6-dimethoxy-pyrimidine, 69 g (0.5 mol) of potassium carbonate and 1500 ml of acetonitrile are mixed with stirring. 33.85 g (0.1375 mol) of O-methyl-isourea sulphate are then added and the mixture is heated to boiling for 17 hours. After cooling, the solution is filtered off with suction and the mother liquor is concentrated. After taking up the residue in methylene chloride, the solution is washed three times with water, dried and concentrated again. 49.9 g of N-(4,6-dimethoxy-pyrimidin-2-yl)-O-methylisourea are obtained in the form of yellow crystals of melting point 91°-95° C. (90% purity; yield 85% of theory).
Reaction SMILES: C([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=3[CH3:27])=[N:14][C:13]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)=[N:12][C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:13]2[N:14]=[C:15]([O:17][C:18]3[C:19]([CH3:27])=[CH:20][C:21]([C:22]#[N:23])=[CH:24][C:25]=3[CH3:26])[C:16]3[NH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(Cc3ccccc3)c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2cc[nH]c12
Temperature: 160 °C
Yield: 26.3 %

Procedure:
To a suspension of 4-(5-benzyl-2-(4-cyanophenylamino)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (240 mg, 0.51 mmol) in 1,2-dichlorobenzene (20 mL) was added AlCl3 (681 mg, 5.1 mmol). The reaction mixture was heated at 160° C. for 1.5 h, during which time the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled and washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC eluting with Hexanes:Ethyl acetate (2.5:1) and produced the product as a pink solid (51 mg, 26%).
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[CH3:11][N:12]([CH2:14][C:15]1[S:19][C:18]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1)[CH3:13].[CH2:25]([NH2:27])[CH3:26]>>[CH3:13][N:12]([CH2:14][C:15]1[S:19][C:18]([CH2:20][S:21][CH2:22][CH2:23][NH:24][C:3]2[C:7]([NH:27][CH2:25][CH3:26])=[N:6][S:5](=[O:10])[N:4]=2)=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCN
Reactant: COC1=NS(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)s1
Product: CCNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)s1

Procedure:
When a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A] is successively reacted with an equimolar amount of 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine and excess ethylamine according to the procedure described in Example 18, the title compound is thereby produced.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[N:37][NH2:38])[NH2:36]>ClCCl.O>[NH2:36]/[C:35](/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)=[N:37]\[NH:38][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16]
Reactant: NN=C(N)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N/N=C(\N)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To as solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 37 g (167 mM) in dichloromethane (300 ml) is added carbonyl diimidazole (1 eq.) in small portion over a period of 30 min. pyridine-2-carbohydrazonamide is then added to reaction mixture and stirred at room temperature for 3 hrs. Dichloromethane is evauporated and reaction mass is then stirred in water for 30 min. solid precipitated is filtered and dried to afford the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20]O)=[N:18][N:17]=[C:16]1[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][N:32]2[C:31](=[O:33])[C:30]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]3[C:28]2=[O:38])=[N:18][N:17]=[C:16]1[CH2:22][CH2:23][N:24]([CH3:25])[CH3:26]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)CCc1nnc(CO)n1-c1ccccc1C(=O)c1ccccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccccc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1B, 2'-chloro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in tetrahydrofuran is treated with phthalimide, triphenylphosphine and diethylazodicarboxylate to give 2'-chloro-2-[3-[2-(dimethylamino)-ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[C:5]([O:7][CH3:8])=[O:6].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C@:22]([OH:37])([C@H:29]([S:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])[CH3:30])[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C@@:22]([OH:37])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:29]([S:31][C@@H:32]1[CH2:33][O:34][C@@H:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[F:1])[O:13][CH2:35]1)[CH3:30].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C@@:22]([OH:37])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:29]([S:31][C@H:32]1[CH2:33][O:34][C@@H:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[F:1])[O:36][CH2:35]1)[CH3:30]
Reactant: COC(=O)c1ccc(C=O)c(F)c1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc([C@H]2OC[C@@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)c(F)c1
Product: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)c(F)c1

Procedure:
In the same manner as that described in Example 3(3), a reaction was carried out using methyl 3-fluoro-4-formylbenzoate (105 mg, 0.58 mmol) obtained in Example 5(1), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (207 mg, 0.58 mmol) and p-toluenesulfonic acid monohydrate (199 mg, 1.04 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-3-fluorobenzoate (trans isomer, 106 mg, yield 35%) and methyl 4-[cis-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-3-fluorobenzoate (cis isomer, 29 mg, yield 10%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].O.[NH2:23][NH2:24]>>[CH2:1]([C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:20])[NH:23][N:24]=3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C)cn1-c1ccc(C(=O)CCC(=O)O)cc1
Reactant: NN
Solvent: O
Product: CCc1nc(C)cn1-c1ccc(C2=NNC(=O)CC2)cc1

Procedure:
Similarly, reaction of 4-(2-ethyl-4-methyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(2-ethyl-4-methyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone (3d).