Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:26])([C:17]([CH3:25])([CH3:24])[CH2:18]OS(C)(=O)=O)[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[C:17]([CH3:24])([CH3:25])[CH2:18][O:26]2)=[CH:8][CH:9]=1
Reactant: CC(C)(COS(C)(=O)=O)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)COC1(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.5 %

Procedure:
160 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 750 mg of 2-(4-chlorophenyl)-3,3-dimethyl-4-methanesulfonyloxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol in 12 ml of dimethylformamide, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with an aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was purified by preparative thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent, to afford 170 mg (yield 31%) of the title compound, melting at 90°-102° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][N:26]([CH3:33])[C:27]2=[O:32]>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[N:25][N:26]([CH3:33])[C:27]3=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Cn1ncc2c(N)cccc2c1=O
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cccc2c(=O)n(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 295 mg (1.0 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 217 mg (1.0 mmol) of 5-amino-2-methylphthalazin-1-one and 0.53 ml of titanium tetraethoxide are reacted to give 5-{[(2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentyliden]amino}-2-methylphthalazin-1-one. 590 mg of resultant crude imine are cyclized, in the same way as in Example 1, at −30° C. using 10 ml (10 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-60%) yields 204 mg of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2c(C)c(-c3ccccc3)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(-c2ccccc2)sc2c(Cl)c(Cl)c(O)cc12
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A mixture of 2.5 g of 6,7-dichloro-5-methoxy-3-methyl-2-phenyl benzo[b]thiophene and 20 g of pyridine hydrochloride is stirred at 185°-190° for 3 hours. The cooled mixture is triturated with water and extracted 3 times with ether. The combined ether extracts is washed with dilute hydrochloric acid, water and dried. Removal of solvent leaves a brownish solid which is purified by passing it through a silica gel column packed in hexane. Elution with 50:50 ether-hexane gave 1.8 g of 6,7-dichloro-5-hydroxy-3-methyl-2-phenylbenzo[b]thiophene as colorless crystals, mp 146°-147°. For analysis, a sample is recrystallized twice from ether-hexane (10% of ether) and dried at 100°.
Reaction SMILES: C1(O[C:8](=[O:27])[CH:9]([C:11]2([OH:26])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[CH2:13][CH2:12]2)[CH3:10])C=CC=CC=1>C(N)CCC>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][C:11]([CH:9]([CH3:10])[C:8]([NH:14][CH2:13][CH2:12][CH2:11][CH3:9])=[O:27])([OH:26])[CH2:16][CH2:15]1
Reactant: CC(C(=O)Oc1ccccc1)C1(O)CCN(CCc2ccccc2Cl)CC1
Solvent: CCCCN
Product: CCCCNC(=O)C(C)C1(O)CCN(CCc2ccccc2Cl)CC1

Procedure:
A solution of 5 g of 2-(1-o-chlorophenethyl-4-hydroxy-4-piperidyl)propionic acid phenyl ester and 50 cc of n-butylamine is boiled at reflux for 18 hours in an atmosphere of nitrogen. The excess n-butylamine is then removed by evaporation at reduced pressure, the residue is taken up in chloroform and the organic phase is washed twice with water and dried over magnesium sulphate. The chloroform is evaporated at reduced pressure. The residue is treated with maleic acid in acetone and the title compound is crystallized from acetone/ether (M.P. of hydrogen maleate 130°-133° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][NH:7]2.[O:16]1COCO[CH2:17]1.Cl>O1CCOCC1>[OH:16][CH2:17][C:5]1[C:4](=[O:15])[C:3]2[C:8](=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:2]=2[CH3:1])[NH:7][CH:6]=1
Reactant: Cc1ccc([N+](=O)[O-])c2[nH]ccc(=O)c12
Reactant: C1OCOCO1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])c2[nH]cc(CO)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a stirred mixture of 1,4-dihydro-5-methyl-8-nitro-4-oxoquinoline (1.5 g) and 1,3,5-trioxane (3.31 g) in dioxane (15 ml) was added conc. hydrochloric acid (30 ml), and the mixture was stirred at 100° C. overnight. The mixture was evaporated in vacuo, and the residue was treated with acetonitrile to give 1,4-dihydro-3-hydroxymethyl-5-methyl-8-nitro-4-oxoquinoline (1.3 g).
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[NH:24][CH3:25].C(OCC)(=O)C>O1CCCC1>[CH3:25][N:24]1[C:15]2[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:22]=[CH:23][C:14]=2[NH:13][C:1]1=[O:2]
Reactant: CNc1cc(C(=O)OC)ccc1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Add carbonyl diimidazole (567 mg, 3.50 mmol) to a solution of methyl 4-amino-3-(methylamino)benzoate (586 mg, 3.19 mmol) in tetrahydrofuran (20 mL) at room temperature. Stir the yellow solution at room temperature for 16 hours. Add carbonyl diimidazole (500 mg, 0.96). Stir at room temperature for 4 hours. Add ethyl acetate (75 mL). Wash with 10% citric acid (5 mL), 1N sodium hydroxide (5 mL), and brine (5 mL). Dry the organics over magnesium sulfate, filter, concentrate, and dry under high vacuum to yield a crude yellow solid (690 mg, 100%). Triturate this crude solid with ethyl acetate (10 mL). Filter the precipitate and dry under high vacuum to yield methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (422 mg, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 3.46 (s, 3 H), 3.92 (s, 3 H), 7.12 (d, J=8.21 Hz, 1 H), 7.68 (s, 1 H), 7.84 (dd, J=8.31, 1.47 Hz, 1 H), 9.87-10.03 (m, 1 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=O.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH:27]([NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:2])([CH3:29])[CH3:28]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Yield: 56 %

Procedure:
As described for example 91h, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (150 mg, 0.42 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (90 mg, 56%) which was obtained as a white solid. MS: m/e=387.0 [M−H]−.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:17][CH2:18][CH3:19])[NH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:6])[CH3:5].[C:20]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:50]2[CH:57]=[CH:56][C:53]([CH2:54]Br)=[CH:52][CH:51]=2)=[N:42][N:41]=[N:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(OCC)(=O)C>[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:17][CH2:18][CH3:19])[N:10]([CH2:54][C:53]2[CH:52]=[CH:51][C:50]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[C:43]3[N:39]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:40]=[N:41][N:42]=3)=[CH:57][CH:56]=2)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:6])[CH3:5]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
48 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to a solution of 0.26 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 5 ml of N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 0.72 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 5 ml of N,N-dimethylformamide was then added, and the reaction mixture was stirred at room temperature for 2 hours and then at 60° C. for 4 hours. At the end of this time, it was dissolved in ethyl acetate and the solution was washed three times with water. The solution was then dried over anhydrous sodium sulfate, after which it was freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.62 g of the title compound as an amorphous solid. This was crystallized from diisopropyl ether, to give the title compound as crystals, melting at 167°-168° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)(O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)(Cl)=O>>[Cl:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)(Cl)c1ccc2cc(OC)ccc2c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(Cl)c1ccc2cc(OC)ccc2c1

Procedure:
A mixture of 0.747 mole of ethyl α-chloro-6-methoxy-2-naphthylglycolate is stirred with 106.67 g. (0.895 mole) of thionyl chloride at room temperature for 24 hours and then heated to reflux for 6 hours. The cold reaction mixture is poured into 1125 ml. of ice-cold water with stirring. The mixture is extracted with 800 ml. of ether. The ethereal solution is washed with 450 ml. of cold saturated sodium hydrocarbonate solution followed by washing twice, each time with 250 ml. of cold water. The ethereal solution is dried over anhydrous sodium sulfate and filtered. The solvent is removed in vacuo to obtain ethyl α-chloro-6-methoxy-2-naphthylacetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:18]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=2[F:16])=[C:2]([CH:3]=1)[O:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(OCc2c(F)cccc2F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C(C)=O)ccc1OCc1c(F)cccc1F

Procedure:
A mixture of 3′-hydroxy-4′-(2,6-difluorobenzyloxy)-acetophenone (15.0 g, 53.96 mmol), ethyl bromoacetate (7.2 mL, 64.75 mmo), and K2CO3 (14.9 g, 107.92 mmol) in acetone (350 mL) is refluxed 18 hours. After cooling, the mixture is filtered, and the filtrate is concentrated in vacuo. Recrystallizaton from EtOAc yields ethyl [5-acetyl-2-(2,6-difluorobenzyloxy)-phenoxy]-acetate.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Br:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[O:22][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(F)c(C)c1
Reactant: CCc1cccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cccc(Oc2ccc(C(=O)OC)cc2C)c1Br
Temperature: 130 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of methyl 4-fluoro-3-methylbenzoate (1.7 g, 10 mmol) and 2-bromo-3-ethylphenol (2.0 g, 10 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (2.8 g, 20 mmol). The reaction mixture was stirred at 130° C. for 3 hours. After the reaction, the mixture was poured into water (50 mL) and the solution was extracted with ethyl acetate (50 mL), washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure to give the pure product methyl 4-(2-bromo-3-ethylphenoxy)-3-methylbenzoate as colorless oil (2.10 g, 60%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].C([Sn]([N:23]=[N+:24]=[N-:25])(CCCC)CCCC)CCC>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[NH:25][N:24]=[N:23][N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCc1ccccn1
Solvent: C1COCCO1
Product: c1ccc(Cc2nnn[nH]2)nc1
Temperature: 25 °C

Procedure:
2-Pyridylacetonitrile (10.0 g; 0.084 moles) was dissolved in p-dioxane (200 mL) and then treated with tributyltin azide (30.9 g; 0.093 moles) in one portion. The solution was refluxed for 20 hours, cooled to room temperature, and then concentrated in vacuo. The viscous syrup was taken up in ethyl ether and treated with gaseous HCl for over 15 minutes, affording a maroon-colored precipitate that was recrystallized from ethanol. Yield: 9.1 g (55%).
Reaction SMILES: [Na].[CH:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[NH:13][CH:14]=[N:15]2>C(O)(=O)C>[CH:2]1([CH2:8][O:9][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[NH:13][CH:14]=[N:15]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OCC1CCCCC1
Reactant: Clc1ncnc2nc[nH]c12
Agent: [Na]
Solvent: CC(=O)O
Product: c1nc(OCC2CCCCC2)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 120 h
Yield: 70 %

Procedure:
Sodium (0.4 g, 17.4 mmol) was added to stirred cyclohexylmethanol (10 ml) under nitrogen. The reaction was stirred at 100° C. until no sodium remained. 6-Chloropurine (500 mg, 3.24 mmol) was added, and the reaction was stirred under nitrogen at 100° C. for 5 days. After cooling to room temperature, the mixture was neutralised with glacal acetic acid and the solvent was removed in vacuo. Water (20 ml) was added and the product was extracted into dichloromethane (3×30 ml). The combined organic extracts were dried over MgSO4, and the volume of the solvent was doubled. After filtering hot and removal of the solvent, recrystallisation from ethyl acetate gave the title compound as a white crystalline solid (600 mg, 70%), m.p. 210-211° C.; (Found: C, 62.30; H, 6.93; N, 24.36. Calc. for C12H16N4O: C, 62.05; H, 6.94; N, 24.12%); νmax (cm−1) 3108, 3050,2930, 2849, 2801 (NH, C—H); δH (200 MHz, d6-DMSO) 8.479 (1H, s, C(2)H or C(8)H), 8.388 (1H, s, C(2)H or C(8)H), 4.348 (2H, d, J=6.2 Hz, OCH2), 1.854-1.692 (6H, m, cyclohexyl), 1.357-0.984 (5H, m, cyclohexyl); δC (50 MHz, d6-DMSO) 159.40, 155, 151.57, 142.88, 118, 71.41 (OCH2), 37.08, 29.40, 26.24, 25.47 (cyclohexyl); m/z 233 (MH+, 76%), 202 (33), 149 ([M—C6H11]+, 32%), 137 (100), 120 ([MH—C7H13O]+, 44%), 108 (30), 93 (27), 81 (65), 67 (62), 55 (88), 41 (89).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([N:20]2[CH2:25][CH:24]=[CH:23][CH2:22][CH2:21]2)[N:14]=1>C(COC)OC>[NH2:19][C:17]1[N+:18]([O-:9])=[C:13]([NH2:12])[N:14]=[C:15]([N:20]2[CH2:21][CH:22]=[CH:23][CH2:24][CH2:25]2)[N:16]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1nc(N)nc(N2CC=CCC2)n1
Solvent: COCCOC
Product: Nc1nc(N2CC=CCC2)nc(N)[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
191 g. of m-chloroperbenzoic acid are dissolved in 800 ml. of dimethoxyethane and cooled to -5° C. 103 g. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine are then added in solid form within 2.5 hours. The mixture is left to warm to room temperature and then stirred overnight. The solvent is then concentrated at 20° C. under reduced pressure and 200 ml. of water are added. The pH value is then adjusted to 10 with sodium hydroxide and the solution is continuously extracted with chloroform for 20 hours. The solvent is then evaporated off and the crude product is chromatographed over silica gel, there being obtained pure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine-3-oxide having a melting point of 261°-265° C. (decomposition).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]([CH3:23])[CH3:22])=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=1)=O)C.Cl.[CH:30]([NH2:32])=[NH:31].CO>CC(O)=O.CN(C=O)C>[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:32]=[CH:30][N:31]=[C:4]([OH:3])[CH:5]=2)=[CH:9][C:10]=1[C:24]([F:27])([F:26])[F:25])([CH3:23])[CH3:22]
Reactant: CCOC(=O)CC(=O)c1ccc(Sc2ccccc2C(C)C)c(C(F)(F)F)c1
Reactant: N=CN
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)c1ccccc1Sc1ccc(-c2cc(O)ncn2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 13.9 %

Procedure:
Then, 6-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-pyrimidin-4-ol 46 was prepared as follows. The mixture of compound 45 (10.6 g, 25.8 mmol) and formamidine hydrochloride (10.4 g, 129 mmol) in 20% HOAc in DMF (50 mL) was heated at 120° C. for 3 days. MeOH (50 mL) was added and the resulting solution was purified on a preparative HPLC column, C8 reverse-phase column, eluted with NH4OAc-H2O—CH3CN. Evaporation of solvents gave a white solid 46 (1.40 g, 14%); MS (APCI) m/z 391 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 87.2 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (4.8 g, 8.03 mmol), NaOH (1.6 g, 40 mmol), H2O (30 mL) and methanol (50 mL) was heated at 80° C. for 1 h. Then methanol was removed under reduced pressure and the aqueous solution was acidified by concentrated hydrochloride to “pH” 1-2. The white precipitate was collected by filtration and dried to give the title compound as a white solid (4 g).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)=[C:21]([CH3:28])[CH:20]=1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Cc1cc(F)ccc1B(O)O
Product: Cc1cc(F)ccc1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 4-fluoro-2-methylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=244.0 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH:29]1[CH2:32][C:31]([C:38]([O:40][CH2:41][CH3:42])=[O:39])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:29]3[CH2:30][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:32]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CCOC(=O)C1(C(=O)OCC)CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Yield: 28571.4 %

Procedure:
A solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.129 g, 0.00042 mmol) in N,N-dimethylformamide (5 mL) was reacted with diethyl 3-[(methylsulfonyl)oxy]-1,1-cyclobutanedicarboxylate (0.150 g, 0.00051 mmol) and cesium carbonate (0.166 g, 0.00051 mmol) at 70° C. for five days. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (98:2). The solvent was removed in vacuo to give diethyl 3-[4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1,1-cyclobutanedicarboxylate (0.060 g, 0.00012 mol) as a tan solid.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[N+:17]([O-])=O)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.S.[NH4+]>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[NH2:17])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(OCC2CCCO2)c([N+](=O)[O-])c1
Agent: S
Agent: [NH4+]
Product: Nc1cc([N+](=O)[O-])ccc1OCC1CCCO1

Procedure:
2,4-Dinitrophenyl tetrahydrofurfuryl ether of the formula II is reduced with alkali metal or ammonium hydrogen sulphide or polysulphide at pH values from 5 to 11, preferably from 9 to 11, and temperatures between room temperature and the boiling point of the reaction mixture, preferably between 60° and 90° C., mainly to give 2-amino-4-nitrophenyl tetrahydrofurfuryl ether of the formula III.