Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)=[O:3].[C:15]([N:19]=[N:20][C:21]([C:27]#[N:28])([CH2:23][CH2:24][CH2:25][OH:26])[CH3:22])([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>CCOCC>[C:15]([N:19]=[N:20][C:21]([C:27]#[N:28])([CH3:22])[CH2:23][CH2:24][CH2:25][O:26][C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)=[O:3])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)N=NC(C)(C#N)CCCO
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)N=NC(C)(C#N)CCCOC(=O)c1ccc2c(c1)C(=O)OC2=O
Reaction time: 0.25 h

Procedure:
To a solution of 2.1 g. (0.01 m) of 4-chloroformylphthalic anhydride in 25 ml ether in a 50 ml 4-neck round bottom flask equipped with a condenser containing a CaCl2 drying tube, a thermometer, a magnetic stirring bar and a dropping funnel was added a solution of 2.0 g. (0.01 m) 2-t-butylazo-2-cyano-5-hydroxypentane (from XIV) and 0.8 g. (0.01 m) pyridine in 10 ml ether. This solution was added dropwise with stirring over 15 minutes holding the temperature between 15° and 22° C with a water bath. The reaction was stirred an additional hour after the addition was completed and the pyridine hydrochloride filtered off. The ether filtrate was dried over anhydrous Na2SO4, filtered and evaporated to dryness leaving 3.1 g. (84%) of a viscous liquid. The infrared spectrum contained 3 carbonyl bands and no OH bands.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([I:29])=[C:25]([OH:30])[CH:24]=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:44][C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[CH2:52][CH2:53]O>C1COCC1>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([I:29])=[C:25]([O:30][CH2:53][CH2:52][C:46]2[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:45]=2[Cl:44])[CH:24]=1
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
6.6 g of triphenylphosphine and 5 g of 4-Iodo-3-hydroxy-benzoic acid methyl ester were dissolved in 65 ml of anhydrous THF. The solution was cooled to 0 ° C. to 10° C. and a solution of 3.7 ml DEAD in 7.5 ml anhydrous THF was added dropwise over 20 min. The reaction was warmed to RT and stirred for 45 min. A solution of 2.8 ml 2-(2,4-Dichlorophenyl)-ethanol in 3 ml anhydrous THF was added with cooling. The reaction was stirred at RT for 3 h, then the solvents were removed under reduced pressure. The residue was treated with n-heptane:ethyl acetate 1:1. The filtrate was dried under reduced pressure. The product was purified by silica gel chromatography, eluting with n-heptane:ethyl acetate/4:1 to n-heptane:ethyl acetate/1:1.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
6-Amino-9-benzyl-2-(isobutylamino)purine (75 mg, 0.25 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent of the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (62 mg, yield 65%).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@H:33]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]([O:36]C(C)(C)C)=[O:35]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@@H:33]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]([OH:36])=[O:35])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Reactant: CCCCCC[C@@H](O)C(=O)OC(C)(C)C
Product: CCCCCC[C@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and tert-butyl (R)-2-hydroxyoctanoate, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 72-74° C.; MS m/e 673 (M−H)+;
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].Cl.[CH2:11]=O>>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][CH2:11][O:5][CH2:4]1
Reactant: OCC(CO)(CBr)CBr
Reactant: C=O
Agent: Cl
Product: BrCC1(CBr)COCOC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 26.2 g of 2,2-bis(bromomethyl)-1,3-propanediol, 50 ml of concentrated hydrochloric acid and 50 ml of 38% formaldehyde was stirred in a 50° C. oil bath overnight, then cooled to room temperature and filtered. The filtrate was extracted with three 100 ml portions of ether. The ether extracts were combined, washed with water, dried and evaporated to an oil. A small amount of solid which formed was removed by filtration and washing with ether. The filtrate and wash were evaporated under reduced pressure, giving 26.9 g of 5,5-bis(bromomethyl)-1,3-dioxane as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:14]([NH:16][C:17]([NH:19][C:20]1[S:21][C:22]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][C:26](B(O)O)=[CH:25][C:23]=2[N:24]=1)=[O:18])[CH3:15]>C1COCC1.O>[Cl:1][C:2]1[N:6]=[C:5]([C:26]2[CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:22]3[S:21][C:20]([NH:19][C:17]([NH:16][CH2:14][CH3:15])=[O:18])=[N:24][C:23]=3[CH:25]=2)[S:4][N:3]=1
Reactant: Clc1nsc(Cl)n1
Reactant: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3nc(Cl)ns3)cc(-c3ccccn3)c2s1
Temperature: 110 °C

Procedure:
3,5-dichloro-1,2,4-thiadiazole (50 mg, 0.32 mmol), Cesium carbonate (285.6 mg, 0.88 mmol), Pd(dppf)2C12 (20 mg, 0.03 mmol) and {2-[(ethylcarbamoyl)amino]-7-(pyridin-2-yl)-1,3-benzothiazol-5-yl}boronic acid (100 mg, 0.29 mmol) was suspended in a mixture of THF (9 mL) and water (1 mL) and heated in the microwave at 110° C. for 50 min. The reaction mixture was concentrated in vacuo and the residue partitioned between 10% IPA/DCM (10 mL) and water (10 mL). The organic layer was separated and the aqueous extracted with further 10% IPA/DCM (3×10 mL), the organic layers were combined, dried (MgSO4), filtered and concentrated, then pre-absorbed onto silica and purified by flash column chromatography (Biotage SP4 12 g, 2% MeoH/DCM-5% MeoH/DCM-8% MeOH/DCM) to give 1-[5-(3-chloro-1,2,4-thiadiazol-5-yl)-7-(pyridin-2-yl)-1,3-benzothiazol-2-yl]-3-ethylurea as a brown solid. (100 mg, 81%) MS: 416.92 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[C@@H:13]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>>[C@@H:13]1([NH:22][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: COc1ccc(C(=O)O)cc1C
Product: COc1ccc(C(=O)N[C@H]2CCc3ccccc32)cc1C
Yield: 63 %

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and (S)-2,3-dihydro-1H-inden-1-amine. Yield 63%. 1H NMR (500 MHz, dMSO): δ 1.94-1.99 (m, 1H), 2.17 (s, 3H), 2.41-2.46 (m, 1H), 2.82-2.87 (m, 1H), 2.96-3.01 (m, 1H), 3.83 (s, 3H), 5.53-5.57 (dd, 1H), 6.98-6.99 (d, 1H), 7.16-7.23 (m, 3H), 7.26-7.27 (m, 1H), 7.75-7.80 (m, 2H), 8.54-8.55 (d, 1H). MS (M+H, 282).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C(C)Br
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)N1CCN(c2ccccn2)CC1

Procedure:
A mixture of 1-(2-pyridyl)piperazine (15.0 grams; 0.092 moles), ethyl 2-bromopropionate (16.7 grams; 0.092 moles) and potassium carbonate (12.7 grams; 0.092 moles) in absolute ethanol (150 cc) is boiled under reflux for about three hours. After cooling, the mixture is filtered, the filtrate is allowed to evaporate and finally the residue is distilled under vacuo, giving the product, b.p. 130°-132° C. (0.01 mm); Rf=0.37 (from ethyl acetate); IR (neat) νmax: 1730, 1600, 1490, 1440, 1320, 1250, 1160, 985, 780 cm-1.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O1CCCC1.C(OCC)(=O)C>[C:15]1([CH2:21][CH2:22][NH:23][C:9]([C@@H:8]2[CH2:13][C@H:11]([SH:10])[CH2:12][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (32.2 mg) in tetrahydrofuran (1 ml) was added 2-phenylethylamine (20.1 mg). The mixture was stirred for 4 hours at room temperature. After the reaction was over, 1N-hydrochloric acid (0.027 ml) was added thereto, and the mixture was diluted with ethyl acetate (2 ml) and dried over magnesium sulfate. Distillation of the solvent, followed by purifying the residue by silica gel chromatography, gave oily (2S,4S) -N-(2-phenylethyl)-1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarboxamide.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH2:25][CH:26]1[O:28][CH2:27]1)=[CH:11][CH:10]=3)[CH3:2].C(O)=[O:30]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH2:25][CH:26]([OH:28])[CH2:27][OH:30])=[CH:11][CH:10]=3)[CH3:2]
Reactant: O=CO
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(OCC4CO4)ccc3nc21
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OCC(O)CO)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-ethyl-6-(2,3-epoxypropoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (0.53 g) and formic acid (10 ml) are stirred at room temperature overnight. The excess formic acid is removed in vacuo and then methanol (75 ml) and triethylamine (10 ml) are added, and the mixture is stirred for four hours. The reaction mixture is evaporated, ether is added, and the product which crystallizes is recrystallized from CH2Cl2 /Et2O and then purified by column chromatography on silca eluting with CH2Cl2 /THF (1/1) to afford 1-ethyl-6-(2,3-dihydroxypropoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin -4-amine, m.p. 197°-199° C.
Reaction SMILES: N1C(C)=CC=CC=1C.[O:9]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])S(C(F)(F)F)(=O)=O.[F:24][C:25]([F:30])([F:29])[CH2:26][CH2:27]O>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[S:17]([O:9][CH2:27][CH2:26][C:25]([F:30])([F:29])[F:24])(=[O:18])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCC(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cold (−25° C.), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in CH2Cl2 (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was then concentrated to half its volume and was then purified by loading directly on a silica gel column (330 g ISCO) and eluting with CH2Cl2. Obtained Preparation A-1M (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2H, t, J=6.15 Hz), 2.49-2.86 (2H, m).
Reaction SMILES: C(O[C:5]1[C:6]([O:12][CH3:13])=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)(=O)C.C[O-:15].[Na+]>CO>[OH:15][CH2:11][C:8]1[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=[CH:10][N:9]=1
Reactant: C[O-]
Reactant: COc1cc(C)ncc1OC(C)=O
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(CO)c1
Yield: 41 %

Procedure:
Starting with 2-methyl-4-methoxypyridine-1-oxide (2.1 g) in the procedure of Part (ii) afforded 2.5 g of 2-acetoxymethyl-4-methoxypyridine which was contaminated with about 25% of 5-acetoxy-2-methyl-4-methoxypyridine. This mixture was dissolved in methanol (10 ml) containing 1.118 g (20.7 mmole) sodium methoxide and stirred at reflux for one hour. The methanol was evaporated in vacuo, the residue diluted with water, neutralized with dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo to give 853 mg (41%) 2-hydroxymethyl-4-methoxypyridine. 1H--NMR(CDCl3)ppm (delta): 3.9 (s, 3H), 4.72 (s, 2H), 5.35 (bs, 1H), 6.7 (dd, 1H), 6.95 (d, 1H), 8.3 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:27][CH:26]=2)=[N:4]1)[CH3:2]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[CH:29][CH:30]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CO)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(C=O)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 70 °C
Yield: 81.1 %

Procedure:
To a stirred solution of N′-[4-(1-ethyl-4-{2-[3-(hydroxymethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea (16.67 g, 85% pure, 29.5 mMol) in CHCl3 (700 mL) was added activated MnO2 (33 g, 380 mMol). The reaction was stirred and refluxed (70° C. oil bath) for 6 h, cooled to RT, filtered through a pad of Celite®, rinsed with CHCl3, and evaporated to dryness under vacuum. Purification by flash chromatography on silica gel (5 to 15% MeOH in (1:1) EtOAc/CHCl3) gave the title product (11.45 g, 81%) as a yellow solid (>95% pure by HPLC): MS (ES) m/e 479.3 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 12.33 (d, J=1.3 Hz, 1H), 10.07 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.11 (d, J=5.1 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 6.95 (d, J=2.0 Hz, 1H), 6.81 (d, J=5.1 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 2.91 (s, 6H), 1.52 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20]2[CH:25]=[N:24][N:23]([CH:26]([CH3:28])[CH3:27])[C:21]=2[N:22]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:26]([N:23]1[C:21]2[N:22]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:18]=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20]=2[CH:25]=[N:24]1)([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1cc(O)nc2c1cnn2C(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
Trifluoromethanesulfonic anhydride (5.23 g, 18.5 mmol) was added to a cooled solution of ethyl 6-hydroxy-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (4.2 g, 16.9 mmol) and pyridine (1.46 g, 18.5 mmol) in DCM (60 mL); and it was allowed to stirred at room temperature for 2 h. After completion of the reaction, saturated NaHCO3 solution (60 mL) was added to it and extraction was carried out using DCM (30 mL×3). The combined organic layers were washed with water (100 mL); brine (100 mL); dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was finally purified by silica gel column chromatography to provide pure the desired intermediate (5 g, 77.8% yield).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]2([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]2([CH2:31][NH:32][C:7]([C:6]3[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:3][C:2]=3[CH3:1])=[O:9])[CH2:27][CH2:28][CH2:29][CH2:30]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)c3cc(-c4ccccc4)oc3C)CCCC2)cc1OC
Reaction time: 16 h
Yield: 20.3 %

Procedure:
2-Methyl-5-phenyl-furan-3-carboxylic acid (40.4 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (17.0 mg, 0.0405 mmol, 20.3%) ESI-MS m/z calc. 419.2, found 420.4 (M+1)+. Retention time of 3.62 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][CH2:25][CH2:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:11][CH:10]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)CCCCl
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCOc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 3 h

Procedure:
116 g (0.5 mole) of 4'-chloro-4-hydroxybenzophenone, 84 g (0.6 mole) of potassium carbonate and 500 cm3 of DMF are placed in a 1 liter flask. The mixture is brought to reflux and 90 g (0.5 mole) of methyl 5-chloro-2,2-dimethylpentanoate in 200 cm3 of DMF are then added from a dropping funnel. Reflux is continued for 3 hours. The mixture is then cooled and poured into 1 liter of water, so that the desired product precipitates. The precipitate is extracted with diethyl ether, washed with aqueous soda, then with water, dried and decolourised, and the solvent is evaporated under vacuum. 160 g of a white solid are obtained, which are recrystallised from diisopropyl ether. 130 g of the desired product are obtained, m.pt. 64° C.
Reaction SMILES: [F:1][C:2]1([F:35])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13]([NH:15][C:16]3[CH:32]=[CH:31][C:19]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([C:27](OC)=[O:28])[CH:22]=4)=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:5]=2[C:4]([F:34])([F:33])[O:3]1.[Cl-].[Mg+2].[Cl-].[NH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>C1COCC1>[N:43]1([CH2:42][CH2:41][CH2:40][NH:39][C:27]([C:23]2[CH:22]=[C:21]([O:20][C:19]3[CH:18]=[CH:17][C:16]([NH:15][C:13]([NH:12][C:10]4[CH:9]=[CH:8][C:6]5[O:7][C:2]([F:1])([F:35])[O:3][C:4]([F:34])([F:33])[C:5]=5[CH:11]=4)=[O:14])=[CH:32][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[O:28])[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: NCCCn1ccnc1
Reactant: COC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(c3)C(F)(F)OC(F)(F)O4)cc2)ccn1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCCn3ccnc3)c2)cc1)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
To a mixture of methyl 4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]-carbonyl}amino)phenoxy]pyridine-2-carboxylate (80 mg, 0.16 mmol) and magnesium chloride (16 mg, 0.16 mmol) in THF (2 ml) was added 1-(3-aminopropyl)imidazole (0.04 mL, 0.32 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 d. The solid was filtered and washed with 10% MeOH in CH2Cl2. The combined filtrate was concentrated to dryness and the residue was purified by column chromatography, eluting with 2 to 5% MeOH/CH2Cl2 to afford 44 mg (45%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.19 (s, 1H), 9.05 (s, 1H), 8.97 (t, 1H), 8.54 (d, 1H), 8.13 (d, 1H), 7.70-7.58 (m, 4H), 7.42 (d, 1H), 7.38 (d, 1H), 7.19-7.16 (m, 4H), 6.87 (s, 1H), 3.97 (t, 2H), 3.24 (q, 2H), 1.95 (quin, 2H); MS LC-MS(MH)+=587.1, RT=3.14 min.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][CH2:12][CH2:13][CH:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:13][CH2:12][NH:11][C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(CCN)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(CCNC(=O)Oc1ccccc1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Phenyl chloroformate (0.132 mL, 1.05 mmol) was added dropwise to tert-butyl 3-amino-1-(4-chlorophenyl)propylcarbamate (Intermediate 25) (300 mg, 1.05 mmol) and sodium bicarbonate (133 mg, 1.58 mmol) in dioxane (10 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 2 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl N-[1-(4-chlorophenyl)-3-(phenoxycarbonylamino)-propyl]carbamate (427 mg, 100%) as a gum.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:29])[C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:19][CH:18]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:12]1([NH:11][C:4]2[C:5]3[CH:10]=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:29])[C:24]([CH:26]4[CH2:27][CH2:28]4)=[O:25])=[CH:21][CH:22]=3)[N:3]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: CN(C(=O)C1CC1)c1ccc(N)cc1
Reactant: Clc1nc(NC2CCC2)c2cc[nH]c2n1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CN(C(=O)C1CC1)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Temperature: 115 °C
Yield: 6.2 %

Procedure:
To a suspension of 2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (67 mg, 0.3 mmol) in nBuOH (0.8 mL) was added N-(4-aminophenyl)-N-methylcyclopropanecarboxamide (85 mg, 0.45 mmol) and TMSCl (0.02 mL, 0.15 mmol). After heating at 115° C. for 2 h, the mixture was cooled and purified by preparative HPLC to give N-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylcyclopropanecarboxamide (7 mg). MS found for C21H24N6O as (M+H)+ 377.2. λ=208.7, 272.4, 304.5.