Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:15](=[O:18])[CH2:16]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([C:15](=[O:18])[CH2:16][N:1]2[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]2[C:7]([O:9][CH3:10])=[O:8])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: COC(=O)[C@H]1COCCN1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H]1COCCN1CC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl (3R)-morpholine-3-carboxylate from Step A (556 mg, 3.83 mmol) and 3,5-difluorophenacyl bromide (450 mg, 1.92 mmol) in CH2Cl2 (2 mL) was added DIPEA (0.669 mL, 3.83 mmol). The reaction mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The crude product was purified on silica gel, eluting with hexane:EtOAc—75:25, to yield the title compound. MS: m/z=300 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:19]=[C:18](F)[C:15]([C:16]#[N:17])=[C:14]([F:21])[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:19]=[C:18]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:15]([C:16]#[N:17])=[C:14]([F:21])[CH:13]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a 500-mL RBF was added NaH (0.660 g, 27.5 mmol) and THF (100 mL). To this solution was added benzyl alcohol (2.385 mL, 22.94 mmol) in THF slowly via syringe, with external cooling (ice bath) when necessary. After the addition, the reaction mixture was stirred for 1 hour at room temperature. At this time, the mixture was transferred via syringe slowly to a solution of 4-bromo-2,6-difluorobenzonitrile (5 g, 22.94 mmol) in THF at 0° C. The solution was allowed to warm to room temperature and stirred over the weekend. The reaction was poured into water (50 mL), and extracted with EtOAc (3×100 mL). The organic layers were combined and dried over Na2SO4. The dried solution was filtered, and the filtrate was concentrated in vacuo to yield a pale yellow solid which was purified by flash chromatography (gradient elution 0-30% EtOAc in hexanes) to afford the title compound (3.911 g) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6): δ 5.35 (s, 2H), 7.27-7.66 (m, 7H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[O:7][CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][C:13](=[O:19])[NH:14]2)([CH3:3])[CH3:2].[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][CH2:27][C:28]1[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=1[CH3:33]>N1CCCC1.C(O)C>[CH3:37][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][C:28]1[C:29]([CH3:36])=[C:30]([CH:34]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[CH2:9][CH2:8][O:7][C:6]3[CH:20]=[CH:21][CH:22]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[NH:14][C:13]2=[O:19])[NH:31][C:32]=1[CH3:33]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Reactant: CC(C)c1cccc(OCCc2cccc3c2CC(=O)N3)c1
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(CCOc4cccc(C(C)C)c4)c32)c(C)c1CCCN(C)C
Temperature: 90 °C
Yield: 86.7 %

Procedure:
A mixture of 4-[2-(3-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one (28 mg, 0.095 mmol), 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (20 mg, 0.095 mmol) and 1 drop of pyrrolidine in 1.0 mL of ethanol was heated at 90° C. for 4 hours and cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane, and dried in a vacuum oven overnight to give 40 mg (87%) of 3-[4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-4-[2-(3-isopropyl-phenoxy)-ethyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[CH2:30])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-])=O)[CH:21]=2)=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([C:16](=[CH2:30])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=2)=[O:18])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: C=C(C(=O)Nc1ccc(O)c([N+](=O)[O-])c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C(=O)Nc1ccc(O)c(N)c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 70 °C
Yield: 53 %

Procedure:
In a 100 ml flask equipped with a refrigerant, 0.9 g (2.18 mmoles) of 3-[(3,5-bis-(1,1-dimethylethyl)4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide is dissolved in 20 ml of ethyl acetate, 2.46 g (10.9 mmoles) of tin chloride (dihydrate) is added and the mixture is heated at 70° C. for three hours. After returning to ambient temperature, the reaction medium is poured onto an agitated solution of sodium bicarbonate (0.1 M), a precipitate forms, which is eliminated by filtration on celite. The filtrate is decanted and the aqueous phase is extracted with 20 ml of ethyl acetate. The organic phases are collected together and washed with 20 ml of water followed by 20 ml of a saturated solution of sodium chloride. After drying over sodium sulphate and filtration, the organic solution is concentrated to dryness, under partial vacuum. The evaporation residue is suspended in a heptane/ethyl acetate mixture (1/1) and filtered to produce a yellowish powder with a yield of 53%. The product is used as it is in the following stage.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.CC(C)([O-])C.[K+].[CH2:28]([OH:31])[CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][O:31][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH2:12][CH2:13][CH3:14])(=[O:11])=[O:10])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1
Reactant: CCCS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(C)cc1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Temperature: 100 °C
Reaction time: 168 h

Procedure:
n-Propanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (489 mg) was added to a solution of potassium tert.-butoxide (900 mg) in ethylene glycol (10 ml). The solution was stirred at 100° C. for 7 days. The reaction mixture was then poured onto ice/water and extracted with ethyl acetate. The crude product was purified by chromatography over silicagel with DCM/MeOH=9/1 to give n-propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (390 mg) as a white powder. LC-MS: tR: 3.76, [M+H]+: 352.13.
Reaction SMILES: CC(C)([O-])C.[K+].C1(S([CH2:16][C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][N:18]=2)(=O)=O)C=CC=CC=1.[N:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][C:36]#[N:37])=[CH:30][CH:29]=1>O1CCCC1>[C:22]1([C:20]2[N:21]=[C:17]3[CH:16]=[C:34]([C:31]4[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=4)[CH:35]=[C:36]([NH2:37])[N:18]3[N:19]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N#CC=Cc1ccncc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccc2)n1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To a boiling suspension of 78.8 g(0.70 mol) potassium tert-butoxide in 400 ml tetrahydrofuran was slowly added over a period of 5 hours a mixture of 70.1 g (0.23 mol) 3-benzenesulfonylmethyl-5-phenyl-1H-[1,2,4]triazole and 30.5 g (0.23 mol) 3-(4-pyridinyl)-2-propenenitrile in 800 ml tetrahydrofuran. Boiling was continued for 18 hours and then the mixture was cooled to room temperature. Evaporation of the solvent and chromatography on silicael with dichloromethane/methanol 95/5 gave 19.8 g (29%) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine as yellow crystals with mp. 207-210° C., MS m/e (%):287 (M+, 100).
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)#[N:13]>CC(C)=O>[CH2:21]([O:20][C:18]([C:17]1[CH:23]=[CH:24][C:14]([C:12]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:13]=2)=[CH:15][CH:16]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1nsc(=O)o1
Reactant: CCOC(=O)c1ccc(C#N)cc1
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2nc(C(=O)OCC)ns2)cc1
Yield: 23.5 %

Procedure:
A solution of 1.75 g (0.010 mol) of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate and 17.5 g (0.10 mol) of ethyl p-cyanobenzoate was stirred at 190° C for 72 hours, cooled, and dissolved in acetone. Gc analysis of the solution revealed that the product had formed in 53% yield. Concentration of the solution to 90° C (0.1 torr) and two crystallizations of the residue from ethanol (charcoal) at -20° C gave 0.72 g (23.5%) of beige solid, mp 66°-67.5° C.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]=[C:19]1[C:24]2=[CH:25][NH:26][C:27]([CH:28]=O)=[C:23]2[CH2:22][CH2:21][NH:20]1.N1CCCCC1>C(O)C>[O:17]=[C:12]1[C:11](=[CH:28][C:27]2[NH:26][CH:25]=[C:24]3[C:23]=2[CH2:22][CH2:21][NH:20][C:19]3=[O:18])[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:9]=2)[NH:13]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2cc(C(=O)N3CCCC3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(C(=O)N3CCCC3)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-(pyrrolidine-1-carbonyl)-1,3-dihydro-indol-2-one (46 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2ncc(Br)cn2)cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
5-bromo-2-iodopyrimidine (0.320 g), 4-(trifluoromethyloxy)phenylboronic acid (FRONTIER SCIEN., 0.231 g), tetrakis(triphenylphosphine)palladium(0) (ALDRICH, 0.026 g) and sodium carbonate (1.6 ml, 2M in H2O) in dry toluene (2.8 ml) was refluxed for 24 hours under argon atmosphere. After cooling to room temperature, H2O (5 ml) was added to the reaction mixture. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with brine, dried over MgSO4, concentrated under vacuum and purified by column chromatography on silica gel, eluting with EtOAc-hexane 1:20 to give 0.248 g of the desired product as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]1)[CH2:2][CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:26][C:27]([F:40])([F:39])[S:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](F)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([N:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][S:35]([C:32]3[CH:33]=[CH:34][C:29]([S:28][C:27]([F:40])([F:26])[F:39])=[CH:30][CH:31]=3)(=[O:37])=[O:36])=[CH:13][CH:14]=2)[CH2:5]1)[CH2:2][CH3:3]
Reactant: O=S(=O)(F)c1ccc(SC(F)(F)F)cc1
Reactant: CCCN1CC[C@@H](c2ccc(N)cc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3ccc(SC(F)(F)F)cc3)cc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
4-((S)-1-Propylpyrrolidin-3-yl)phenylamin (50 mg, 0.24 mmol) was dissolved in THF (5 ml) at −78° C. and potassium hexamethyldisilazide (146 mg, 0.73 mmol) added. The solution was stirred at −78° C. for 1 hour and then 4-(trifluoromethylthio)benzene-1-sulfonyl fluoride (64 mg, 0.24 mmol) was added and the solution was allowed to reach room temperature over night. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and NaOH (2M). The organic extract was separated, dried (MgSO4), filtered and concentrated to give the product (97 mg, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([CH:15]=[C:16]1[NH:20][N:19]=[C:18]([C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])[O:17]1)=[O:14])[CH3:11]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([C:18]3[O:17][C:16](=[CH:15][C:13]([O:12][CH2:10][CH3:11])=[O:14])[NH:20][N:19]=3)[CH:22]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CCOC(=O)C=C1NN=C(c2cccc(N)c2)O1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CCOC(=O)C=C1NN=C(c2cccc(Nc3nc(Cl)ncc3F)c2)O1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)aniline gave 2-chloro-N4-[3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-4-pyrimidineamine. 1H NMR (CD3OD): δ 8.42 (t, 1H, J=1.8 Hz), 8.19 (d, 1H, J=3.3 Hz), 7.99 (dt, 1H, J=1.2 and 8.1 Hz), 7.82 (dt, 1H, J=1.2 and 8.1 Hz), 7.58 (t, 1H, J=9 Hz), 4.24 (q, 2H, J=3.9 Hz), 4.17 (s, 2H), 1.28 (t, 3H, J=7.2 Hz); LCMS: purity: 85%; MS (m/e): 379 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C1COCC1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][C:33]=3[F:42])[N:30]=[CH:31][C:24]=12>C(Cl)Cl>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:23]2[N:28]=[CH:27][N:26]=[C:25]3[N:29]([C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][C:33]=4[F:42])[N:30]=[CH:31][C:24]=23)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500 mL round-bottomed flask equipped with a N2 inlet septum was placed a stir bar, NaH (60% in mineral oil, 1.8 g, 45.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.53 g, 7.6 mmol). THF (anhydrous, 80 mL) was added to the mixture. The resulting suspension was stirred about 30 min at room temperature. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 7.6 mmol) was then added in one portion. The mixture was stirred overnight under N2 at room temperature and the resulting slurry turned slightly yellowish. The slurry was added CH2Cl2 and filtered. The filtrate was concentrated under vacuum to give the crude product. Column chromatography purification using 50% EtOAc/Hexane gave Compound A74 as an off-white solid. Exact mass calculated for C22H26FN5O5S: 491.16, found 492.1 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:22]([O:29][C:30](=[O:37])[C@@H:31]1[CH:35]([Br:36])[CH2:34][CH2:33][NH:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.ClCCl>[CH2:22]([O:29][C:30](=[O:37])[C@@H:31]1[CH:35]([Br:36])[CH2:34][CH2:33][N:32]1[C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)[C@H]1NCCC1Br
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N[C@@H](CCC(=O)O)C(=O)N1CCC(Br)[C@H]1C(=O)OCc1ccccc1

Procedure:
A solution of 20 mmoles of pyro-L-glutamic acid and 20 mmoles of 3-bromo-proline benzyl ester toluene sulfonic acid, neutralized with N-ethyl morpholine, in dichloromethane: DMF(4:1) is cooled in an ice bath with stirring. A solution of 20 mmoles of dicyclohexylcarbodiimide in dichloromethane is ddded to the above reaction mixture. The reaction mixture is stirred in an ice water bath for one hour and then at room temperature overnight. Dicyclohexylurea is removed by filtration and the product is washed in ethyl acetate. Solvents of the combined filtrates are removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate is added to the residue and the organic solution is washed until neutral. The organic phase is dried over anhydrous MgSO4, filtered and then the solvent is removed with a rotary evaporator. The material is crystallized from isopropanol and ether yielding the named product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:37])[C:15]3[CH:20]=[CH:19][C:18]([O:21]CC4C=CC=CC=4)=[C:17]([O:29]CC4C=CC=CC=4)[CH:16]=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[N:3]=1>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:37])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:29])[CH:16]=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[N:3]=1
Reactant: COc1ccc(Cc2cc(C3CCN(C(=O)c4ccc(OCc5ccccc5)c(OCc5ccccc5)c4)CC3)nc(N)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2cc(C3CCN(C(=O)c4ccc(O)c(O)c4)CC3)nc(N)n2)cc1
Yield: 74.3 %

Procedure:
2-Amino-4-[1-(3,4-dibenzyloxybenzoyl)-4-piperidinyl]-6-(4-methoxyphenylmethyl)pyrimidine (293 mg, 0.48 mmol) was dissolved in a mixture of methanol (3 ml) and ethyl acetate (3 ml), and hydrogenated under 1 atm in the presence of 10% palladium on carbon (80 mg) for about 3 hours. The catalyst was filtered off and washed with methanol. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (chloroform:methanol=97:3) to give the titled compound (155 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 37 %

Procedure:
Commercially available 4-fluorobenzenesulfonyl chloride (1.00 g, 5.14 mmol) was suspended in water (15 mL), and N-methylpiperazine (0.68 mL, 6.17 mmol) and potassium carbonate (1.56 g, 11.3 mmol) were added, followed by stirring at room temperature for 14 hours under nitrogen atmosphere. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL), and subsequently the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-90%) to afford the desired compound (491 mg, yield 37%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41].C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:36]3[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:34]([O:33][CH3:32])[CH:35]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc3n2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and 3,4,5-trimethoxy phenylboronic acid (112 mg, 0.527 mmol) in N,N-dimethylformamide (2630 μl) was added saturated aqueous bicarbonate solution (880 μl) followed by bis(triphenylphosphine)palladium dichloride (17.26 mg, 0.025 mmol). The mixture was heated to 70° C. for 4 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 610.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2.C(=O)([O-])[O-].[K+].[K+].[CH2:40](Br)[CH:41]=[CH2:42]>CC(C)=O>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20][CH2:42][CH:41]=[CH2:40])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: C=CCBr
Reactant: Cc1cc(O)c(C(=O)CCc2ccc3occc3c2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C)cc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1C(=O)CCc1ccc2occc2c1
Temperature: 0 °C
Yield: 60 %

Procedure:
3-(5-Benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (2.50 g) is dissolved in acetone (20 ml), and thereto are added potassium carbonate (2.13 g) and allyl bromide (933 mg), and the mixture is refluxed for 6 hours. After cooling, the reaction mixture is poured into ice-water, and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 3-(5-benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-allyloxy-4'-methylpropiophenone (1.63 g).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)[NH2:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[C:26](=[O:33])N(CCO)N=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:1]([C:3]3[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=3)[N:2]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1ccc(CC(=O)O)cc1
Product: COc1ccc(C2=NN(c3ccc(CC(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 4-hydrazinophenylacetic acid as described for compound 35. Crystallized from diethyl ether. M.p. 162° C.