Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3](OCC)=[O:4].[NH2:31][C:32](N)=[S:33].C([O-])(=[O:37])C.[Na+].Cl>O.C(O)C>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:20][C:19]=1[CH2:18][CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH:2]2[S:33][C:32](=[O:37])[NH:31][C:3]2=[O:4])=[CH:15][CH:14]=1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(Cl)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC2SC(=O)NC2=O)cc1
Yield: 55.7 %

Procedure:
A mixture of ethyl 2-chloro-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate (0.20 g), thiourea (0.145 g), sodium acetate (0.115 g) and ethanol (15 ml) was heated under reflux for 30 hours. 6N hydrochloric acid (15 ml) was added, and the mixture was heated under reflux for 15 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with methanol-chloroform (2:98, v/v) gave 5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]ethyl]-2,4-thiazolidinedione (0.11 g, 56%). This product was recrystallized from dichloromethane-ethanol. Colorless prisms, mp: 151-152° C.
Reaction SMILES: [NH2:1][C@@:2]1([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:7][O:6][C@@H:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][C@H:3]1[CH2:17]O.C([N:35]=[C:36]=[S:37])(=O)C1C=CC=CC=1.Cl>ClCCl.CO>[CH2:10]([O:9][CH2:8][C@@H:5]1[O:6][CH2:7][C@@:2]2([C:19]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=3[F:26])[C@H:3]([CH2:17][S:37][C:36]([NH2:35])=[N:1]2)[CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
[(2R,4R,5S)-5-Amino-2-benzyloxymethyl-5-(5-bromo-2-fluorophenyl)tetrahydropyran-4-yl]methanol (2.22 g) was dissolved in dichloromethane (30 ml), and benzoyl isothiocyanate (776 μl) was added. The mixture was stirred at room temperature for five hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain an intermediate. The resulting intermediate was dissolved in methanol (50 ml), and concentrated hydrochloric acid (2 ml) was added. The mixture was heated under reflux for six hours and then cooled to room temperature. The solvent was evaporated under reduced pressure. Methanol (30 ml) and DBU (2 ml) were added to the residue, followed by heating under reflux for three hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (2.30 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>N1C=CC=CC=1>[CH3:16][N:17]([CH3:21])[C:18]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1ccc2c(c1)C(=O)NC(=O)C2(C)C

Procedure:
1.3 g. (6.3 mMole) 7-amino-4,4-dimethylisoquinoline-1,3-dione was dissolved in 30 ml. pyridine, mixed, while cooling with ice, with 1.5 g. dimethylcarbamoyl chloride and the reaction mixture further stirred for 4 hours at 25° C. Subsequently, the reaction mixture was distilled to dryness, the residue was taken up in methylene chloride, washed with water, dried and the methylene chloride distilled off. The residue was recrystallised from ethanol. Yield 1.1 g. (63.6% of theory); m.p. 256°-258° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O.[NH2:48][C:49]1[NH:53][N:52]=[N:51][N:50]=1>CN(C=O)C.O>[CH:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=3)[N:9]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:48][C:49]4[NH:53][N:52]=[N:51][N:50]=4)=[O:30])=[CH:31][CH:32]=3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc(Cn2nc(C3CCCCC3)cc2-c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of 70 mg product from Step A above, 38.1 mg EDC, 26.9 mg HOBt in 1 mL DMF was stirred at room temperature for 30 minutes. 5-Aminotetrazole monohydrate (20.5 mg) was added and the mixture stirred for additional 16 hours. Precipitate the product by adding 1 mL water to the reaction mixture. Collect the product by filtration, wash it with 1:1 DMF and water, water, and MeCN, and dry to give the title compound as a white solid. 1H NMR (CD3OD, 600 MHz) δ 7.92 (d, J=8.4 Hz, 2H), 7.42˜7.45 (m, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 6.32 (s, 1H), 5.42 (s, 2H), 2.67 (tt, J=3.5 & 11.5 Hz, 1H), 1.97˜2.01 (m, 2H), 1.81˜1.85 (m, 2H), 1.72˜1.76 (m, 1H), 1.46˜1.53 (m, 2H), 1.38˜1.47 (m, 2H), 1.26˜1.35 (m, 1H). LC-MS: 2.30 min. (M+H=512.3).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>CN1CCCC1=O>[CH:26]1([CH2:25][N:3]2[C:2]([N:29]3[CH2:34][CH2:33][N:32]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:31][CH2:30]3)=[N:10][C:9]3[C:4]2=[N:5][C:6]([C:17]2[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[N:7][C:8]=3[N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:28][CH2:27]1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: CS(=O)(=O)Cl
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCN(S(C)(=O)=O)CC3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
N-Methylpyrrolidone (2 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (200 mg, 0.50 mmol) and piperazine (430 mg, 5.0 mmol) and the resulting mixture was stirred at 120° C. for 2 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in tetrahydrofuran (2 ml) followed by the addition of triethylamine (140 μl, 1.0 mmol) and mesyl chloride (50 μl, 0.65 mmol) and the resulting mixture was stirred for 1 hour. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (135 mg, 51%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10](SC)=[C:11](O)[CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C[S:31]([CH3:33])=O>CCCCCC.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:9])=[C:33]([CH:8]=2)[S:31][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: CS(C)=O
Reactant: CSc1ccc(Oc2ccc(Br)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CSc1cc(Oc2ccc(Br)cc2)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromophenoxy)-2-(methylthio)phenol (0.05 mole), potassium carbonate (0.2 mole), methyl 2-bromoacetate (0.08 mole) and dimethylsulfoxide (200 ml) are charged into a 500 ml glass reaction flask equipped with a mechanical stirrer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into 500 ml of water. The resulting mixture is extracted three times with 100 ml portions of methylene chloride. The extracts are then combined, washed with water and therafter dried. The dried solution is then stripped of solvent under reduced pressure to leave a residue. The residue is subjected to chromatography using a clay column and hexane/ethyl acetate mixture as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product methyl 2-[5-(4-bromophenoxy)-2-methylthiophenoxy]acetate as the residue.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([Mg]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: Clc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2ccccn2)cc1
Temperature: 50 °C
Yield: 97.9 %

Procedure:
216.5 g (3.0 mol) of tetrahydrofuran (THF), 113.5 g (1.0 mol) of 2-chloropyridine and 0.24 g of Pd(dppf)Cl2 (0.03 mol %) are placed in a flask and heated to 50° C. while stirring. 510 g of phenylmagnesium chloride solution in THF (27% strength) are slowly metered in while cooling externally so that the temperature does not exceed 50° C. The mixture is then stirred for another 90 minutes at this temperature. It is slowly hydrolyzed with 250 g of water and allowed to cool to room temperature. After phase separation, the aqueous phase is stirred with 250 ml of tert-butyl methyl ether. After renewed phase separation, the organic phases combined and the reaction mixture is evaporated at 150 mbar. It is subsequently distilled at atmospheric pressure until a bottom temperature of 80° C. has been reached. The distillation residue is distilled at 10 mbar, giving 152.0 g of 2-phenylpyridine (98.1%), purity: 98.7% (according to GC).
Reaction SMILES: [CH3:1][C@H:2]([CH2:19][CH2:20][CH:21]([OH:26])[C:22](O)([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8].[BrH:27].O.C(=O)(O)[O-].[Na+].[C:34]([OH:37])(=O)[CH3:35]>>[CH3:1][C@H:2]([CH2:19][CH2:20][CH:21]([O:26][C:34](=[O:37])[CH3:35])[C:22]([Br:27])([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8]
Reactant: C[C@@H](CCCn1c(=O)c2c(ncn2C)n(C)c1=O)CCC(O)C(C)(C)O
Reactant: CC(=O)O
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(CC[C@@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O)C(C)(C)Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(4-(S)-Methyl-7,8-dihydroxy-8-methylnonyl)-3,7-dimethylxanthine (0.37 g, 1.00 mmol) was stirred with hydrogen bromide (1.25 mL of a 30% solution in acetic acid, 3.00 mmol) for 4 hours. The mixture was then added over 10 minutes to water (10 mL), ice (5 g) and sodium bicarbonate (2 g) and stirred for 30 minutes. The reaction mixture was extracted with dichloromethane (2×15 mL), and the combined organic phases were dried using magnesium sulfate and the solvent evaporated to yield a residue of 1-(4-(S)-methyl-7-acetoxy-8-bromo-8-methylnonyl)-3,7-dimethylxanthine.
Reaction SMILES: [C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].[I-:14].[Na+]>C(#N)C>[C:1](=[O:13])([O:2][CH:3]([I:14])[CH3:4])[O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(I)OC(=O)OC1CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
9.15 g of cyclohexanol was dissolved in 150 mL of methylene chloride, to which 7.4 mL of pyridine was added followed by dropwise addition of 10 mL of 1-chloroethyl chloroformate in an ice bath, and this mixture was stirred for 2 hours at room temperature. Then, a sodium chloride solution was added to the reaction mixture and the organic phase was separated therefrom. After the resultant organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled out under reduced pressure to yield 18.6 g of 1-chloroethyl cyclohexyl carbonate as colorless oil. 5.00 g of this 1-chloroethyl cyclohexyl carbonate was dissolved in 150 mL of acetonitrile, to which 16.3 g of sodium iodide was added, and this mixture was stirred for one hour at 60° C. The mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out therefrom by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 5.90 g of cyclohexyl 1-iodoethyl carbonate as red oil.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][CH:9]2[CH2:14][CH:13]=[CH:12][CH2:11][CH2:10]2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[CH2:15]=C(C)C>>[CH:8]([CH:9]1[CH2:10][CH2:11][CH:12]=[CH:13][CH2:14]1)=[C:7]([CH3:1])[CH3:15].[CH:7]([CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)=[CH2:8]
Reactant: C1=CCC(C=CC2CC=CCC2)CC1
Reactant: C=C(C)C
Product: C=CC1CC=CCC1
Product: CC(C)=CC1CC=CCC1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
13.1 g of the catayst prepared in Example 17 was charged into a steel reactor under a blanket of nitrogen. To this was added 8.4 g of 1,2-dicyclohex-4-enyl ethylene and 27 g of isobutene. The reactor was sealed and rocked. After 1 hour at ambient temperature, the products were analysed. 3.7% of the 1,2-dicyclohex-4-vinyl ethylene was converted affording dismutation products with the following selectivities 31.3% 4-isobutenylcyclohexene and 69.% 4-vinylcyclohexene.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH:24]([CH3:26])[CH3:25])[N:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH3:26][CH:24]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1)[CH3:25]
Reactant: CC(C)n1nc(-c2ccc(OCc3ccccc3)cn2)c2ncccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)n1nc(-c2ccc(O)cn2)c2ncccc21
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of 3-[5-(benzyloxy)pyridin-2-yl]-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (219 mg) and 10% Pd—C (50% wet, 73.1 mg) in MeOH (3 mL) and AcOEt (3 mL) was hydrogenated under balloon pressure at room temperature overnight. The solid was filtrated and washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to give the title compound (140 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][CH:26]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc3ccccc23)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 1-naphthylboronic acid according to the general procedure B. Obtained as a yellow foam (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH:31]1([C:34]#[C:35][C:36](O)=[O:37])[CH2:33][CH2:32]1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:36](=[O:37])[C:35]#[C:34][CH:31]3[CH2:33][CH2:32]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: O=C(O)C#CC1CC1
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)C#CC3CC3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Yield: 26 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and 3-cyclopropylpropiolic acid, to afford the title compound (8 mg, 26%). Data: UPLC (C) Rt: 1.73 min; m/z 492.3 (M+H)+.
Reaction SMILES: ClC1C=CC(S(Cl)(=O)=O)=CC=1[N+]([O-])=O.COC1C=CC=CC=1N.Cl[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])(=[O:33])=[O:32])=[CH:27][C:26]=1[N+:43]([O-:45])=[O:44].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>C(Cl)Cl.N1C=CC=CC=1>[CH3:42][O:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)=[C:26]([N+:43]([O-:45])=[O:44])[CH:27]=1)(=[O:33])=[O:32]
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Agent: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1ccc(N2CCN(C)CC2)c([N+](=O)[O-])c1

Procedure:
The compound was prepared from 4-chloro-3-nitrobenzenesulfonylchloride (1 g, 3.9 mmol), 2-methoxyaniline (0.53 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2Cl2 (2 mL). 4-Chloro-N-(2-methoxyphenyl)-3-nitrobenzenesulfonamide (0.345 mg) was reacted with N-methylpiperazine (0.144 mL) to afford N-(2-methoxyphenyl)-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide which was treated with Raney-Ni and hydrazine monohydrate. The final product was isolated as its HCl salt 1H NMR (DMSO-d6) δ 7.185 (dd, 1H), 7.08 (dt, 1H), 6.975 (d, 1H), 6.91-6.94 (m, 2H); 6.84 (dt, 1H), 3.56 (s, 3H), 3.42-3.47 (m, 2H), 3.22-3.24 (m, 2H), 2.95 (bt, 2H), 2.79 (bs, 3H); MS (posESI) m/z=376.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][N:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=3)=[C:6]2[N:5]=[C:4]([CH:22]2[CH2:27][CH2:26][C:25]([CH2:29][OH:30])([OH:28])[CH2:24][CH2:23]2)[C:3]=1SC.[C:33]([O-])(O)=O.[Na+].O[O:39][S:40]([O-:42])=O.[K+]>CO.O>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][N:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:15]=3)=[C:6]2[N:5]=[C:4]([CH:22]2[CH2:27][CH2:26][C:25]([CH2:29][OH:30])([OH:28])[CH2:24][CH2:23]2)[C:3]=1[S:40]([CH3:33])(=[O:42])=[O:39]
Reactant: CSc1c(C2CCC(O)(CO)CC2)nc2c(-c3cnn(-c4ccccc4)c3)cnn2c1N
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1c(C2CCC(O)(CO)CC2)nc2c(-c3cnn(-c4ccccc4)c3)cnn2c1N
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 18.7 %

Procedure:
To a solution of 4-(7-amino-6-(methylthio)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol (32.0 mg, 0.0710 mmol) in a mixed solvent of MeOH/H2O (2/0.5 mL) was added NaHCO3 (23.8 mg, 0.284 mmol), followed by Oxone (87.3 mg, 0.142 mmol) at rt. The resulting mixture was stirred at 40° C. for 2.5 h. The reaction mixture was filtered and washed with DMF and MeOH. The combined filtrate was concentrated and purified by a reverse phase HPLC to afford 4-(7-amino-6-(methylsulfonyl)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol as a white solid (6.4 mg). HPLC-MS TR=4.08 min (UV 254 nm, 10 min method); mass calculated for formula C23H26N6O4S 482.2, observed LCMS m/z 483 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.ClCCl.O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cccc(Br)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1-(6-bromopyridin-2-yl)ethanone (2.9636 g, 14.82 mmol) in methanol (40 mL) at 0° C. was charged with sodium borohydride (1.682 g, 44.4 mmol) and then allowed to warm to room temperature. After 2.5 hours, the reaction mixture was diluted with dichloromethane (60 mL) and water (60 mL) and the layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:32]4[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=4)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:40]1[CH2:44][C:43](=[O:45])[NH:42][C:41]1=[O:46]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:32]4[CH:39]=[CH:38][C:35]([CH:36]=[C:44]5[S:40][C:41](=[O:46])[NH:42][C:43]5=[O:45])=[CH:34][CH:33]=4)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A solution of toluene (6 mL), piperidine (10 μL), acetic acid (10 μL), 4-[3-(1-adamantyl)-4-methoxyphenyl]benzaldehyde (0.337 g, 0.97 mmol) and 2,4-thiazolidinedione (0.114 g, 0.97 mmol) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, and the resulting crystalline compound was filtered, washed with toluene and ethanol. The yellow solid was dried under high vacuum to afford 0.375 g (87%) of 4-[3-(1-adamantyl)-4-methoxyphenyl]benzylidene-2,4-thiazolidinedione, mp 304–306° C. 1H NMR (300 MHz; DMSO-d6): 1.75 (s, 6H), [2.06 (s), 2.11 (s), 9 H], 3.85 (s, 3H), 7.09 (d, J=8.7 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.57 (dd, J=8.7 Hz, J=2.3 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.82 (s, 1H), 12.4–12.7 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[CH:12]\[CH2:13][NH:14][C:15](=[O:17])[CH3:16])=[CH:5][CH:4]=1>FC(F)(F)C(O)=O.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH:8]=[C:9]2[CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: COc1ccc2c(c1)/C(=C/CNC(C)=O)CC2
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)C(CCNC(C)=O)=CC2
Yield: 90.1 %

Procedure:
The (E)-N-[2-(6-methoxyindan-1-ylidene)ethyl]-acetamide (1.0 g, 4.32 mmol) thus obtained was dissolved in trifluoroacetic acid(6 ml)-tetrahydrofuran(6 ml) and the solution was refluxed for 1.5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed serially with saturated saline and water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol=96:4) to provide the title compound (yield 0.9 g, 90%).