Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>>[Cl:14][C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)nn1
Product: O=C(O)c1ccc(Cl)nn1
Temperature: 25 °C
Yield: 100 %

Procedure:
Potassium dichromate (3.3 g, 11.2 mmol) was added in portions to a solution of 3-Chloro-6-methyl-pyridazine (1.2 g, 9.3 mmol) in H2SO4 (10 ml). After addition the mixture is stirred at 50° C. on. The reaction was pored on ice and the mixture was extracted three times with diethyl ether. The combined organic phases were dried and concentrated to give the title compound (840 mg, 57%). LC-MS (M++1): 159 and 161 (3:1). Step 2: 6-Chloro-pyridazine-3-carboxylic acid methyl ester: A solution of 6-chloro-pyridazine-3-carboxylic acid (700 mg, 4.53 mmol) in thionyl chloride (15 ml) was refluxed for 3 h. The reaction was cooled to ambient temperature and evaporated to dryness. Sodium methoxide (244 mg, 4.53 mmol) in MeOH (20 ml) was added to the residue and the solution was stirred on at room temperature (rt). H2O was added and the mixture was extracted three times with DCM. The combined organic phases were dried and concentrated. Flashchromatography (SiO2, Heptane/EtOAc 1:1) afforded 560 mg (72%) of the title compound. 1H NMR (CDCl3), δ (ppm): 4.09 (s, 3 H), 7.69 (d, 1 H), 8.18 (d, 1 H).LC-MS (M++1): 173 and 175 (3:1). Step 3: 6-Methoxy-pyridazine-3-carboxylic acid methyl ester: A solution of 6-chloro-pyridazine-3-carboxylic acid methyl ester in NaOMe in MeOH (1M, 10 ml) was refluxed on. H2O was added and the mixture was extracted three times with DCM to give organic phase I. The combined organic phases I were dried and concentrated to give the title compound (40 mg, 10%). The water phase was acidified with concentrated hydrochloric acid and extracted three times with DCM to give organic phase II. The combined organic phases II were dried and concentrated to give 6-methoxy-pyridazine-3-carboxylic acid (LC-MS (M++1): 155) (230 mg, 65%). A solution of 6-methoxy-pyridazine-3-carboxylic acid in thionyl chloride (6 ml) was refluxed for 3 h. The reaction was cooled to ambient temperature and evaporated to dryness. MeOH (10 ml) was added to the residue and the solution was stirred on at rt. Saturated NaHCO3 (aq) was added and the mixture was extracted three times with DCM. The combined organic phases were dried and concentrated to give the title compound (253 mg, 100%).LC-MS (M++1): 169. Step 4: 4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione: NaOMe (86 mg, 1.6 mmol) was added to a solution of 6-methoxy-pyridazine-3-carboxylic acid methyl ester (210 mg, 1.25 mmol) and 4-ethyl-3-thiosemicarbazide (190 mg, 1.6 mmol) in MeOH (6 ml) and the mixture was heated to 70° C. at 72 h. The reaction was cooled to ambient temperature and evaporated to dryness. H2O (10 ml) was added to the residue and the mixture was acidified with concentrated hydrochloric acid and the title compound 35 mg (12%) was collected by filtration. LC-MS (M++1): 238.
Reaction SMILES: [CH3:1][C:2]([N+:9]([O-])=O)([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][OH:7]>CO.[Ni].O>[NH2:9][C:2]([CH3:8])([CH3:1])[CH2:3][NH:4][CH2:5][CH2:6][OH:7]
Reactant: CC(C)(CNCCO)[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(C)(N)CNCCO
Reaction time: 19 h
Yield: 78 %

Procedure:
To a solution of 2-((2-methyl-2-nitropropyl)amino)ethanol (20.4 g, 126 mmol) in methanol (120 ml) was added a slurry of 50% Raney Nickel® in H2O (6 ml). The vessel was pressurized with H2 (450 psi) and the suspension stirred for 19 h. The mixture was filtered through Celite and concentrated in vacuo to give 20 g of a crude liquid, which was distilled under vacuum (<1 mbar, 100-125° C.) to give 13 g of a clear liquid, which was found to be partially purified and was used directly in the next step without purification. LRMS (ESI/APCI) m/z 133 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:24])=[O:23])=[CH:17][C:16]=2[F:25])=[C:11]([O:26][CH2:27][CH3:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:39])([F:40])[F:41])[CH:31]=3)=[O:23])=[CH:17][C:16]=2[F:25])=[C:11]([O:26][CH2:27][CH3:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(N)=O)cc1F
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1F
Yield: 28.3 %

Procedure:
A solution of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)acetamide (20 mg, 0.053 mmol), 4-bromo-2-(trifluoromethyl)benzonitrile (13.14 mg, 0.053 mmol), Pd2(dba)3 (4.81 mg, 5.26 μmol), Xantphos (3.04 mg, 5.26 μmol) and Cs2CO3 (34.3 mg, 0.105 mmol) in 1,4-dioxane (2 mL) was stirred at 120° C. for 1 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (20 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=2/1) to yield 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-3-fluorophenyl)-N-(4-cyano-3-(trifluoromethyl)phenyl)acetamide (12 mg, 0.015 mmol, 28.5% yield): 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 7.59-7.48 (m, 1H), 7.43-7.28 (m, 5H), 7.23-7.15 (m, 2H), 6.46 (s, 1H), 5.34 (s, 2H), 4.09 (m, 2H), 3.73 (s, 3H), 1.28 (t, J=6.4 Hz, 3H); ES-LCMS m/z 550.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9].C(OC([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=O)(C)(C)C.C(N(CC)CC)C.Cl>C(O)C.O1CCOCC1>[ClH:1].[N:17]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:8][OH:9])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: OCc1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: OCc1cnccc1N1CCNCC1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-3-hydroxymethylpyridine (J. Med. Chem., 49 (13), 2832-2840 (2002))(143 mg, 1 mmol), 1-(tert-butoxycarbonyl)piperazine (186 mg, 1 mmol) and triethylamine (1 mL, 7 mmol) were dissolved in ethanol(3 mL), and the mixture was stirred overnight in a threaded test tube at 130° C. The solvent was evaporated and work-up according to a conventional method gave a crude product. The obtained crude product was dissolved in a dioxane solution (5 mL) containing 4 N hydrogen chloride, and the mixture was stirred for 2 hrs. The solvent was evaporated to give the title compound, which was used for the synthesis of C-22 and C-37.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4](=[CH2:10])[CH:5]([OH:9])[CH2:6][CH2:7][CH3:8].[C:12](OC(=O)C)(=[O:14])[CH3:13].Cl>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4](=[CH2:10])[CH:5]([O:9][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH3:8]
Reactant: C=C(C(=O)OC)C(O)CCC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Product: C=C(C(=O)OC)C(CCC)OC(C)=O
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A mixture of 3-hydroxy-2-methylenehexanoic acid methyl ester (55.37 g, 350 mmol) and DMAP (4.28 g, 35 mmol) in toluene (400 mL) is cooled to 0-5° C. and to it is added acetic anhydride (42.88 g, 420 mmol) dropwise in ˜30 minutes while maintaining the temperature at 0-5° C. The resulting solution is allowed to warm to room temperature in 1 hour. After stirring for 3 hours at RT, the reaction mixture is cooled to 0-5° C. and to it is added 1 N HCl acid (80 mL), in 20 minutes. The organic layer is separated and washed sequentially with water (80 ml), saturated aqueous sodium bicarbonate solution (2×80 mL) and water (80 mL). The organic layer is concentrated on Rotavap under reduced pressure (20 mbar) until no further solvent distills to afford 3-acetoxy-2-methylenehexanoic acid methyl ester (68.39 g, yield: 97.5%) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:32][C:33]2[C:38]([Cl:39])=[CH:37][N:36]=[C:35](Cl)[N:34]=2)=[C:24]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH:25]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:32][C:33]2[C:38]([Cl:39])=[CH:37][N:36]=[C:35]([NH:18][C:4]3[C:3]([O:2][CH3:1])=[CH:17][C:7]4[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=4[CH:5]=3)[N:34]=2)=[C:24]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:27])=[O:28])[CH:25]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: CN(C)S(=O)(=O)c1cc(Cl)ccc1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(Cl)cc4S(=O)(=O)N(C)C)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 5-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan foam (0.061 g, 49%). MP: 59-79° C. 1H NMR (400 MHz, CDCl3, ppm): 9.22 (s, 1H), 8.47 (d, 1H, J=8.8 Hz), 8.14 (s, 1H), 7.92 (s, 1H), 7.86-7.84 (m, 1H), 7.51-7.46 (m, 2H), 6.65 (s, 1H), 3.87 (s, 3H), 3.58-3.53 (m, 2H), 3.38 (s, 3H), 2.92-2.87 (m, 2H), 2.79-2.68 (m, 14H). MS: 595.17 (MH)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)[CH3:2].[F:25][C:26]([F:31])([F:30])S([O-])=O.[Na+].ClCCCl.C(OO)(C)(C)C>CS(C)=O.O>[CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])=[O:15])=[C:12]([C:26]([F:31])([F:30])[F:25])[C:7]=2[NH:6][N:5]=1)[CH3:2]
Reactant: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Reactant: O=S([O-])C(F)(F)F
Agent: CC(C)(C)OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCCl
Product: CCNc1n[nH]c2c(C(F)(F)F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C

Procedure:
(R)-1-(3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (50 mg, 0.154 mmol) and sodium trifluoromethanesulfinate (72.2 mg, 0.462 mmol) were taken in a solvent mixture containing DCE:water:DMSO in a ratio of 2.5:1:0.5, cooled to 0° C. and added tert-butyl hydroperoxide (0.107 mL, 0.771 mmol) and reaction gradually warmed to room temperature. After two more additions of tert-butyl hydroperoxide in equal concentrations in a span of 36 hours, the reaction was partitioned between DCM and aqueous sodium bicarbonate. The organics were washed with brine, dried with sodium sulfate and concentrated. Purification of residue by flash column (0-15% MeOH-DCM) gave (R)-1-(3-(ethylamino)-7-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI [M+H]+ calc'd. 393. found 393. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.40-7.30 (m, 4H), 7.20 (m, 1H), 7.10 (s, 1H), 4.97 (m, 1H), 3.29, (m, 2H), 1.38 (d, J=6.5 Hz, 3H), 1.25 (t, J=7.0 Hz, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH2:18]([N:20](CC)CC)C.CN.CO>C(Cl)(Cl)Cl>[CH3:18][NH:20][CH2:6][CH2:7][S:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)OCCSc1cccc2nccn12
Agent: CN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNCCSc1cccc2nccn12
Yield: 47.1 %

Procedure:
A solution of 5-[2-(methylsulfonyloxy)etylthio]imidazo[1,2-a]pyridine (2.18 g, 8 mmoles), triethylamine (2.24 ml, 16 mmoles) and a 40% methylamine-methanol solution (20 ml) in chloroform (20 ml) was heated at reflux for 3 hours. The reaction mixture was washed with 3N NaOH and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent:methanol/chloroform (1:10)] to obtain 781 mg of the desired product (47.1%, light brown oily product ).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:19]2[N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:21]=[C:22]3[C:27]=2[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][N:6]=3)=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:21]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)nc1

Procedure:
In analogy to the procedure described in example 63.3, [rac]-6-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-nicotinic acid methyl ester was treated with NaOH in MeOH to give the title compound as off-white solid. MS: m/e=480.0 [M+H+].
Reaction SMILES: [Ti:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Ti+4].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9]>S(=O)(=O)(O)O>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Ti+4:1].[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[O-2:3].[Ti+4:1].[O-2:3]
Reactant: [Ti]
Agent: [Ti+4]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: [O-2]

Procedure:
A titanium sulfate solution was prepared by dissolving titanium-containing ore in sulfuric acid. This titanium sulfate solution was hydrolyzed to give aqueous titanium oxide, and added to 100 parts by mass (in terms of TiO2) of this aqueous titanium oxide were 0.50 parts by mass of ammonium phosphate, 0.30 parts by mass of potassium sulfate, and 0.30 parts by mass of aluminum sulfate. The resulting mixture was heated in a laboratory rotary muffle furnace until the product temperature reached 1020° C. The resulting titanium dioxide fine particles were allowed to cool to room temperature and were observed on a transmission electron microscopic photograph that the particles were an anatase type and had an average primary particle diameter of 0.13 μm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:14][C:7]=2[C:6]=1[OH:22])=[O:4].[Cu][C:24]#[N:25]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:24]#[N:25])[C:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:14][C:7]=2[C:6]=1[OH:22])=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(-c3ccc(F)cc3)csc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2c(-c3ccc(F)cc3)csc2c1O
Temperature: 150 °C
Yield: 30.1 %

Procedure:
A mixture of 4-bromo-3-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid methyl ester (58.5 mg, 0.153 mmol), example 32-a, and copper(I) cyanide (27.4 mg, 0.306 mmol) suspended in 1.5 mL of DMF was heated at 150° C. for 30 minutes. The resultant mixture was partitioned between ethyl acetate and water, and the organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-20% methanol in methylene chloride to produce 15.1 mg of a white solid. MS: (+) m/z 329.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.[H-].[Na+].[H-].[CH3:24][N:25](C)[CH2:26]CO>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH2:20][N:25]([CH3:26])[CH3:24])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CN(C)CCO
Reactant: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
To a mixture of ethyl 7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate in 2-dimethylamino ethanol is added sodium hydride. After the hydride is reacted the mixture is heated on a steam bath for 6 hours. The solvent is removed and the residue acidified with dilute acetic acid to give the product of the example.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21]Cl)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C-:24]#[N:25].[Na+]>CC#N.C1OCCOCCOCCOCCOCCOC1>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:23])[C:9]([CH2:21][C:24]#[N:25])=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(C)c(CCl)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CCc2c(C)c(CC#N)c(C)c(NC(=O)C(C)(C)C)c21
Yield: 75.9 %

Procedure:
N-(1-Acetyl-5-chloromethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (21 g) was suspended in CH3CN (150 ml), and NaCN (8.1 g) and 18-crown-6 (870 mg) were added, which was followed by refluxing for 15 hr. CH3CN was evaporated under reduced pressure and CHCl3 (300 ml) was added. The mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The obtained residue was washed with boiling MeOH to give 15.5 g of N-(1-acetyl-5-cyanomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][N:12]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:5]2[C:4](=[O:13])[N:3]=1
Reactant: BrCCCCCBr
Reactant: NCC1=C2C(=O)N=C(N)N=C2N=C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1=NC(=O)C2=C(CN3CCCCC3)C=NC2=N1
Temperature: 25 °C
Reaction time: 96 h
Yield: 30.6 %

Procedure:
In 4.5 ml of methanol were dissolved 151 mg of 2-amino-5-aminomethylpyrrolo[2,3-d]pyrimidin-4-one (dihydrochloride) and 138 mg of 1,5-dibromopentane, followed by addition of 2.4 ml of 1 N-sodium hydroxide. The mixture was stirred at room temperature for 4 days. The solvent was then distilled off under pressure and the residue was purified by silica gel column chromatography. The fractions containing the desired compound were pooled and after addition of an excess of hydrogen chloride/ethanol, concentrated to dryness, followed by precipitation with ether to give 45 mg of the desired compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH2:40])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH2:45]([O:52][C:53]([N:55]1[CH2:60][CH2:59][N:58]([C:61](=[O:68])[C:62]([C:65](O)=[O:66])([CH3:64])[CH3:63])[CH2:57][CH2:56]1)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:40][C:65](=[O:66])[C:62]([C:61]([N:58]3[CH2:59][CH2:60][N:55]([C:53]([O:52][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:54])[CH2:56][CH2:57]3)=[O:68])([CH3:64])[CH3:63])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C(=O)O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCNC(=O)C(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (0.5 g) in N,N-dimethylformamide (10 mL) were added 1-benzyloxycarbonyl-4-[2-carboxy-2-(methyl)propionyl]piperazine (0.28 g), 1-hydroxybenzotriazole (0.22 g), triethylamine (0.18 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=30/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]-carbonyl}-2-(methyl)propionylamino]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.3 g). This material was dissolved in methanol (4 mL). To the solution was added sodium methoxide (28% methanol solution, 0.06 mL), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added acetic acid (0.035 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (0.23 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:23](=[O:24])[N:22]([CH3:25])[C:14]3[N:15]=[C:16](S(C)=O)[N:17]=[CH:18][C:13]=3[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29]C=1>>[CH:25]1([N:22]2[C:14]3[N:15]=[C:16]([NH:31][CH:30]4[CH2:29][CH2:27][CH2:33][CH2:32]4)[N:17]=[CH:18][C:13]=3[CH:12]=[C:11]([S:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)(=[O:10])=[O:9])[C:23]2=[O:24])[CH2:4][CH2:3][CH2:2][CH2:7]1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cn1c(=O)c(S(=O)(=O)c2ccc(Cl)cc2)cc2cnc(S(C)=O)nc21
Product: O=c1c(S(=O)(=O)c2ccccc2)cc2cnc(NC3CCCC3)nc2n1C1CCCC1

Procedure:
The title compound was prepared according to the procedure of Example 3, substituting 8-cyclopentyl-2-(methylsulfinyl)-6-(phenylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one for 6-(4-chlorophenylsulfonyl)-8-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one, and substituting cyclopentylamine for 4-chloroaniline.