Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3N3CCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 1.3 h
Yield: 98.7 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.17 g of piperidine, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for two hours, and then at 80° C. for 1.3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.34 g of 2-[3-(piperidine-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 54”).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:17])=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])=[O:7])(C)(C)C.Cl.[CH2:19](O)[CH3:20]>>[Cl:17][C:11]1[S:10][C:9]([S:6](=[O:7])(=[O:8])[NH2:5])=[C:13]([C:14]([O:16][CH2:19][CH3:20])=[O:15])[CH:12]=1
Reactant: CCO
Reactant: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1C(=O)O
Agent: Cl
Product: CCOC(=O)c1cc(Cl)sc1S(N)(=O)=O
Yield: 96 %

Procedure:
A solution of 2-(N-tert-butylsulfamoyl)-5-chlorothiophene-3-carboxylic acid (60.0 g; 0.201 mol) made by the procedure described by B. Unterhalt and S. Moghaddam, Pharmazie 49, 115-117 (1994) in 700 ml of abs. ethanol saturated with hydrogen chloride was heated with stirring at reflux for 17 h. The cooled solution was evaporated to dryness and the residue was purified by trituration with water and dried to give 52.3 g (96%) of the title compound; 1H-NMR (DMSO-d6): δ 1.31 (t, J=7 Hz, 3H, CH3), 4.32 (q, J=7 Hz, 2H, CH2), 7.55 (s, 1H), 7.77 (br. s, 2H, NH2).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:36](OC(=O)C)(=[O:38])[CH3:37].[OH-].[Na+]>O>[NH:2]([C:36]([CH3:37])=[O:38])[C@@H:3]([C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1

Procedure:
The previously obtained chloromethylene solution of HCl, H-D-Lys(Z)-D-Pro-OBzl is cooled down to 5° C., added with 135 ml of water, followed by 32.3 ml of acetic anhydride (1.5 eq). At Qsp pH 10 is then added within 30 minutes to 1 hour an aqueous 5N NaOH (90 to 130 ml are required).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11](Cl)[CH:10]=[CH:9]2)=[O:5])C.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[O:18][CH3:17])[CH:10]=[CH:9]2)=[O:5]
Reactant: CCOC(=O)c1ccc2nc(Cl)ccc2c1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)c1ccc2nc(NCc3ccccc3OC)ccc2c1
Temperature: 120 °C
Yield: 9.4 %

Procedure:
A stirred mixture of 2-chloro-quinoline-6-carboxylic acid ethyl ester [CAS-No. 29969-56-0] (236 mg, 1.0 mmol) and commercially available 2-methoxy-benzylamine (412 mg, 3.0 mmol) was heated in a sealed tube for 16 h at 120° C. Purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization of each of the two fractions (dichloromethane/hexane) yielded the title compound as a white solid (40 mg, 9%), MS (ISP) 428.3 [(M+H)+]; m.p. 217° C. as well as 2-(2-methoxy-benzylamino)-quinoline-6-carboxylic acid ethyl ester as a white solid (196 mg, 58%), MS (ISP) 337.3 [(M+H)+]; m.p. 108° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:21][CH2:22][CH:23]=C)[C:9](=C)[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[O:4]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[CH3:1][O:2][C:3]([C:5]12[CH2:21][CH2:22][CH:23]=[C:9]1[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:6]2)=[O:4]
Reactant: C=CCCC1(C(=O)OC)CN(C(=O)OCc2ccccc2)CC1=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COC(=O)C12CCC=C1CN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.2 %

Procedure:
The Second Generation Grubbs' catalyst (29.6 mg, 0.871 mmol) was added to a solution of 1-benzyloxycarbonyl-3-(3-buten-1-yl)-4-methylenepyrrolidine-3-carboxylic acid methyl ester (286 mg, 0.871 mmol) in dichloromethane (8.71 mL) in a nitrogen atmosphere. The mixture was stirred at room temperature for 19 hours, and the dichloromethane (17.4 mL) was added. After stirring at 45° C. for six hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→87:13→85:15→83:17→80:20→75:25→66:34) to give 187 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:16]>CO>[NH2:16][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: N
Solvent: CO
Product: Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 45 °C

Procedure:
2,4-dichloro-3-nitroquinoline (5.3 g, 0.218 mol) was combined with 75 mL of 15 percent ammonia in methanol and the mixture was heated at about 45° C. for about 4 hours. The reaction mixture was cooled to room temperature, and the precipitated product was removed by filtration. The volume of methanol was reduced to about 35 mL, and the precipitated product was removed by filtration. The volume of methanol was then reduced to about 10 mL and the precipitated product was again removed by filtration. The combined solids were stirred in aqueous sodium bicarbonate, filtered, and dried to afford a solid product 4-amino-2-chloro-3-nitroquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH2:10](Cl)[C:11]#[CH:12].[OH-].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:12][C:11]#[CH:10]
Reactant: C#CCCl
Reactant: Cc1cccc(C)c1N
Agent: [Na+]
Agent: [OH-]
Product: C#CCNc1c(C)cccc1C

Procedure:
2,6-Dimethylaniline (12.1 g, 0.1 mole) and propargyl chloride (3.8 g, 0.05 mole), were mixed and heated over a steam bath using an efficient reflux condenser for 8 hours, then treated with aqueous caustic soda solution, extracted with ether, the ethereal layer worked up and the residue distilled to give 2,6-dimethylphenyl propargylamine, b.p. 56°-58° C./0.01 mm.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[C:17]([CH2:16][CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:6]=1[C:4]([OH:3])=[O:5])([OH:19])=[O:18]
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2ccccc12
Product: O=C(O)CCc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 3-(2-ethoxycarbonyl-ethyl)-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 372.4 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:23]=[C:22]([C:24]([O:26]C)=[O:25])[NH:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[NH:21][N:20]=2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(-c2cc(Cl)c(OCc3ccc(OC)cc3)c(Cl)c2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(COc2c(Cl)cc(-c3cc(C(=O)O)[nH]n3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a mixture of methyl 3-(3,5-dichloro-4-(4-methoxybenzyloxy)phenyl)-1H-pyrazole-5-carboxylate (0.75 g, 1.85 mmol) in a mixture of THF (10 mL) and methanol (10 mL) was added 15% w/v solution of sodium hydroxide (5 mL). The mixture was stirred at room temperature for 30 minutes followed by heating at reflux for 2 h. After this time the flask was cooled to room temperature and solvent was removed in vacuo. The residue was partitioned between ethyl acetate (20 mL) and water (100 mL). The aqueous layer was acidified to pH 1 (10 M HCl, 1.5 mL) and the precipitated solids dissolved in ethyl acetate (30 mL). The organic layer was washed with an aqueous solution of sodium chloride (65 mL) and dried (MgSO4). The solution was concentrated to give 0.69 g (96%) of the Compound C as a white solid. 1H NMR δ (ppm) (DMSO-d6): 3.81 (3H, s), 5.02 (2H, s), 7.00 (2H, d, J=8.24 Hz), 7.41 (1H, s), 7.48 (2H, d, J=8.24 Hz), 8.03 (2H, s), 14.09 (1H, br s). CO2H peak not observed.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[N:7]=1)=[O:5])C.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH3:25])[C:4]([C:6]1[O:10][N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[N:7]=1)=[O:5])[CH3:22]
Reactant: CCOC(=O)c1nc(/C=C/c2ccc([N+](=O)[O-])o2)no1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1nc(/C=C/c2ccc([N+](=O)[O-])o2)no1
Yield: 57 %

Procedure:
trans-5-Ethoxycarbonyl-3-(5-nitrofur-2-ylvinyl)-1,2,4-oxadiazole (332 mg.) was heated under reflux with diethylamine (5 ml.) for 30 min. to give a deep red solution. Evaporation gave a red solid; recrystallisation from methanol (3 ml.) gave trans-5-diethylcarbamoyl-3-(5-nitrofur-2-ylvinyl)1,2,4-oxadiazole (208 mg., 57%), m.p. 118°-119°, λmax. (EtOH) 240 and 349 nm. (ε18,600 and 19,900), νmax. (CHBr3) 1665 (CONEt2), 1510, 1352 (NO2) and 960 cm.-1 (trans CH=CH).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[Si:8]([O:15][C@H:16]([C@H:19]1[C@@H:22]([C:23]#[C:24][S:25]C2C=CC=CC=2)[NH:21][C:20]1=[O:32])[CH2:17][CH3:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].O>C(Cl)Cl.C(OCC)(=O)C>[Si:8]([O:15][C@H:16]([C@H:19]1[C@@H:22]([CH2:23][C:24]([C:3]2[CH:2]=[CH:18][CH:17]=[CH:16][CH:19]=2)=[S:25])[NH:21][C:20]1=[O:32])[CH2:17][CH3:18])([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1C#CSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1CC(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 152.5 %

Procedure:
Trifluoroacetic acid (0.58 ml, 7.51 mmol) was added to a solution of the compound (564 mg, 1.50 mmol) prepared in Example 6 in methylene chloride (10 ml) at 0° C. in an argon atmosphere. The mixture was stirred for two hours at this temperature and one hour at room temperature. After the addition of sodium hydrogencarbonate (189 mg, 2.25 mmol), water (7 ml), and ethyl acetate (28 ml), the mixture was stirred at room temperature for 40 minutes and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in this order and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to obtain 432 mg (yield 73%) of the title compound as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23]C4CCCCO4)[CH:17]=[CH:16][N:15]=3)=[O:13])[CH2:9]2)=[CH:4][C:3]=1[O:30][CH3:31].Cl.[OH-].[Na+].C([O-])(O)=O.[Na+]>O1CCCC1>[OH:23][CH2:22][CH2:21][O:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]([N:10]2[CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:30][CH3:31])[CH:4]=3)[CH2:11]2)=[O:13])[CH:19]=1
Reactant: COc1cc(C2CN(C(=O)c3cc(OCCOC4CCCCO4)ccn3)C2)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C2CN(C(=O)c3cc(OCCO)ccn3)C2)ccc1O
Temperature: 25 °C
Reaction time: 13 h
Yield: 75 %

Procedure:
To a solution of the crude [3-(4-hydroxy-3-methoxyphenyl)azetidin-1-yl]-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]pyridin-2-yl}-methanone prepared in (1) in THF (5.0 mL) was added 1 N hydrochloric acid (5.0 mL). The reaction mixture was stirred at RT for 13 hr. To the reaction mixture were added aqueous 1 N NaOH and saturated aqueous NaHCO3 and then the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=9/1) to give the title compound (0.70 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:7]2.[N+:16]([C:19]1[CH:20]=[C:21]([C:28](Cl)=[O:29])[CH:22]=[C:23]([C:25](Cl)=[O:26])[CH:24]=1)([O-:18])=[O:17]>N1C=CC=CC=1.O1CCOCC1.C(Cl)(Cl)Cl>[N+:16]([C:19]1[CH:20]=[C:21]([C:28]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:7]3)=[O:29])[CH:22]=[C:23]([C:25](=[O:26])[NH:1][C:2]2[C:3]3[C:8](=[CH:7][C:6]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:5][CH:4]=3)[CH:9]=[CH:10][CH:11]=2)[CH:24]=1)([O-:18])=[O:17]
Reactant: Nc1cccc2cc(S(=O)(=O)O)ccc12
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccc2cc(S(=O)(=O)O)ccc12)c1cc(C(=O)Nc2cccc3cc(S(=O)(=O)O)ccc23)cc([N+](=O)[O-])c1
Reaction time: 1.5 h

Procedure:
22.33 g (0.10 mol) of 5-amino-2-naphthalenesulfonic acid was suspended in 150 mL of pyridine and added to the above di-acid chloride in 50 mL (50:50) of dioxane and CHCl3 under vigorous stirring for 1-2 hrs. The crude product was precipitated with dioxane. The oily product was collected on a Büchner funnel. The brown colored oily product was dissolved in 500 mL water, then allowed to precipitate out over 30 min. The solid material was collected using filtration. It yielded 16.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]1([CH2:37]O)[CH2:36][CH2:35][CH:34]=[CH:33][CH2:32]1.[K+].[Br-].Cl>>[CH3:30][C:31]1([CH2:37][O:24][C:23]([C:18]2([C:20]([O:22][CH2:30][C:31]3([CH3:37])[CH2:36][CH2:35][CH:34]=[CH:33][CH2:32]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:36][CH2:35][CH:34]=[CH:33][CH2:32]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC1(CO)CC=CCC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1(C)CC=CCC1)(C(=O)OCC1(C)CC=CCC1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 1-methylcyclohex-3-enylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.84 (s, 6H, 2×CH3), 1.09 (d, J=6.4 Hz, 3H, CH3), 1.25-1.4 (m, 4H, CH2), 1.6-1.65 (m, 2H, CH2), 1.8-2.0 (m, 6H, CH2), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (m, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 5.55-5.65 (m, 4H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.8 (brs, 1H, NH), 9.4 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); MS m/e 638 (M+H)+ ; Analysis for: C36H44ClNO7 ×HCl: Calc'd: C, 64.09; H, 6.72; N, 2.08; Found: C, 64.69; H, 7.19; N, 1.67.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31])=[CH:26][CH:25]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:30](=[O:31])[C:29]([O:28][C:27]3[CH:35]=[CH:36][C:24]([Cl:23])=[CH:25][CH:26]=3)([CH3:34])[CH3:33])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)N1CCN(c2nc(N)nc3sc(-c4cccnc4)nc23)CC1
Yield: 45 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 2-(4-chlorophenoxy)-2-methylpropanoic acid in a yield of 45%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:28][CH3:29])[C:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:15]2[CH:14]=[CH:13][CH:12]=1.[H-].[Na+].CC1C=CC(S(O[CH2:43][CH:44]2[CH2:47][CH2:46][O:45]2)(=O)=O)=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:28][CH3:29])[C:19]([N:20]([CH2:43][CH:44]3[CH2:47][CH2:46][O:45]3)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NC(=O)OC(C)(C)C)c(SC)nn12
Reactant: Cc1ccc(S(=O)(=O)OCC2CCO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CCO3)C(=O)OC(C)(C)C)c(SC)nn12
Reaction time: 0.5 h

Procedure:
After dissolving tert-butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (100 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 15 mg) was added while cooling on ice, the mixture was stirred for 30 minutes, 2-oxetanylmethyl 4-methyl-1-benzenesulfonate (70 mg) was added and the mixture was stirred for 1 hour at 40° C. 2-Oxetanylmethyl 4-methyl-1-benzenesulfonate (23 mg) [CAS No. 115845-51-7] and sodium hydride (60%, 5 mg) were again added, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure to obtain crude tert-butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)carbamate. This was dissolved in ethyl acetate (2 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (8 mg) was obtained from the n-hexane:ethyl acetate (3:1) fraction as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH:11]C(C)=O)=[CH:10][C:4]=2[O:3]1.C[O-].[Na+]>CO>[CH3:1][C:2]1([CH3:18])[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH2:11])=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)O2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2cc(N)c([N+](=O)[O-])cc2O1
Yield: 92.7 %

Procedure:
22.0 g of 2,2-dimethyl-5-acetamino-6-nitro-1,3-benzodioxole were boiled under reflux for 1 hour in 1.1 of methanol containing 2.2 g of sodium methoxide (10% by weight). After evaporating the solution, the residue was dissolved in methylene chloride, filtered first through Decalit and then through silicon dioxide evaporated and crystallized from isopropanol. There were obtained 17.0 g (92.8% of theory) of 2,2-dimethyl-5-amino-6-nitro-1,3-benzodioxole of melting point 128°-129° C.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]([NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH2:11][CH2:10]1>CN1CCCC1=O>[C:1]([NH:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:17])[NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@H]1CC[C@H](NC(=O)NC2CCCCC2)CC1
Reactant: CC(C)(C)N=C=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)NC(=O)NC1CCC(NC(=O)NC2CCCCC2)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A solution of tert-butylisocyanate (1.17 g, 0.012 mol) in dry N-methyl-2-pyrrolidone (NMP) (50 mL) was added slowly to a solution of trans-1-(4-aminocyclohexyl)-3-cyclohexylurea (2.83 g, 0.012 mol) in dry NMP (100 mL) under inert atmosphere. The resulting mixture was heated to 70° C. and stirred for 24 h. The solution was precipitated in 1 M HCl and filtered off. The resulting white solid was washed with THF, recrystallized from DMF and dried under high vacuum.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH:9]([NH:12][C:13]1[C:18]([CH2:19][NH:20][C:21]2[CH:22]=[C:23]([CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=2)[C:24]#[N:25])=[CH:17][N:16]=[C:15]([S:32][CH3:33])[N:14]=1)([CH3:11])[CH3:10]>CCN(CC)CC>[CH:9]([N:12]1[C:13]2=[N:14][C:15]([S:32][CH3:33])=[N:16][CH:17]=[C:18]2[CH2:19][N:20]([C:21]2[CH:22]=[C:23]([CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=2)[C:24]#[N:25])[C:4]1=[O:3])([CH3:11])[CH3:10]
Reactant: CSc1ncc(CNc2cc(C#N)cc([N+](=O)[O-])c2)c(NC(C)C)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C(C)C)C(=O)N(c1cc(C#N)cc([N+](=O)[O-])c1)C2
Yield: 50.8 %

Procedure:
Diphosgene (5 mL, 41 mmol), 3-((4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methylamino)-5-nitrobenzonitrile (2.2 g, 6.15 mmol) and Et3N (2.5 mL) were combined by the procedure of Example A4 step 3 to give 3-(1-isopropyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-5-nitrobenzonitrile (1.2 g, 51% yield), which was used in the next step without further purification.