Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.C[O-].[Na+].[CH3:29][O:30][CH:31]([O:35][CH3:36])N(C)C>CO>[CH3:29][O:30][CH:31]([O:35][CH3:36])[N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([C:16]2[NH:15][CH:19]=[CH:18][N:17]=2)[CH2:21]1
Reactant: COC(OC)N(C)C
Reactant: c1c[nH]c(C2CCCNC2)n1
Agent: C[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC(OC)N1CCCC(c2ncc[nH]2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture containing the dihydrochloride salt of 3-(1H-imidazol-2-yl)piperidine (0.99 g, 0.0044 M) and methanol (10 ml) which contained sodium methoxide (0.009 M) was stirred at room temperature for 10 min. and dimethylformamide dimethylacetal (10 ml) was added and heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed to give 3-(1H-imidazol-2-yl)-1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (0.77 g, 0.0035 M) and diisopropyl ethylamine (0.42 ml) in CHCl3 (30 ml) was added the chloroform solution (30 ml) of the above piperidine carboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr and then at room temperature for 3 hrs. After this period, the solvent was removed and the residue dissolved in water (30 ml). The aqueous solution, washed with ethylacetate, was acidified to pH 3 with dilute aqueous HCl and purified on Sephadex LH20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[3-(1H-imidazol-2-yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.52 g, 28.8% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]3[C:11]4[CH2:26][CH2:25][CH2:24][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH:17]4[C:21](O)=[O:22])[N:15]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.[N:27]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]3[C:11]4[CH2:26][CH2:25][CH2:24][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH:17]4[C:21]([NH:33][C:31]4[CH:32]=[N:27][CH:28]=[N:29][CH:30]=4)=[O:22])[N:15]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cncnc1
Reactant: O=C(O)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cncnc1)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 3 %

Procedure:
To a solution of 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylic acid (300 mg, 0.847 mmol) in DMF (4 mL) was added pyrimidin-5-amine (201 mg, 2.11 mmol), HATU (386 mg, 1.016 mmol) and DIPEA (0.24 mL, 1.4 mmol). The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with water (8×30 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford 11 mg of 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(pyrimidin-5-yl)pyrrolidine-2-carboxamide as free base. 1H NMR (400 MHz, CD3OD, formate salt) δ (ppm): 0.58-0.67 (m, 2H), 0.80-0.94 (m, 2H), 1.70-1.78 (m, 1H), 2.09-2.21 (m, 4H), 2.22-2.42 (m, 2H), 2.78-2.81 (m, 2H), 2.82-2.95 (m, 2H), 3.60-2.70 (m, 1H), 3.78-3.88 (m, 1H), 4.78 (dd, 1H), 6.08 (s, 1H), 8.84 (s, 1H), 8.89 (s, 2H). Separation by chiral HPLC provided enantiomers 7a and 7b.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][C:43]([N:45]([CH3:53])[C:46]2[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=2)=[O:44])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][C:43]([N:45]([C:46]2[CH:51]=[CH:50][C:49]([NH:52]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:48][CH:47]=2)[CH3:53])=[O:44])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CN(C(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CCN2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-(4-tert.butoxycarbonyl-piperazin-1-yl)-ethyl)-carbonyl)-N-methyl-p-phenylenediamine Rf value: 0.8 (silica gel, methylene chloride/methanol=5:1) C36H41N5O6
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:22])([F:21])[C:8]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:12])([F:11])[F:10].O>N1C=CC=CC=1>[F:6][C:7]([F:21])([F:22])[C:8]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:10])([F:12])[F:11]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
Add 2.50 g (22 mmole) of methanesulfonyl chloride dropwise to 5.06 g (15 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)-aniline in 25 ml of pyridine and allow to stand overnight. Pour the reaction into H2O and extract with Et2O. Wash the Et2O with 1N HCl and extract with 1N NaOH. Acidify the NaOH and extract with Et2O. Dry, concentrate and recrystallize from Et2O-hexane to obtain 4'-(hexafluoro-2-hydroxy-2-propyl)methanesulfonanilide; m.p. 137°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21](O)[CH3:22])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[CH3:20].CN(C)C=O.S(Cl)([Cl:31])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([Cl:31])[CH3:22])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(Cl)cc(C(C)O)c2c1CN(C(=O)OC(C)(C)C)CCO2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(C)Cl)c2c1CN(C(=O)OC(C)(C)C)CCO2
Yield: 99.9 %

Procedure:
A mixture of tert-butyl 7-chloro-9-(1-hydroxyethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (280 mg, 0.82 mmol) and N,N-dimethylformamide (30 μL) in methylene chloride (6 mL) was stirred and thionyl chloride (120 μL, 1.7 mmol) was added dropwise. The mixture was stirred at room temperature for 20 minutes. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired product (295 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH2:16][CH:17]3[CH2:19][CH2:18]3)=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[CH:17]1([CH2:16][NH:15][C:13]([C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:30]([NH:29][C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)=[O:31])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:14])[CH2:19][CH2:18]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(C(=O)NCC3CC3)c2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc(C(=O)NCC3CC3)c2)cc1
Reaction time: 1 h

Procedure:
After adding 100 mg of 4-(4-Aminophenoxy)-2-[(cyclopropylmethyl)aminocarbonyl]pyridine to 5 ml of tetrahydrofuran, 0.075 ml of p-fluorophenyl isocyanate was added at room temperature and the mixture was stirred for 1 hour. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=1:1, followed by ethyl acetate and ethyl acetate:methanol=10:1). The solvent was distilled off under reduced pressure, ethyl acetate and hexane were added to the residue, and the precipitated solid was filtered out to obtain 25 mg of the target substance as a light yellow powder.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:24])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32]>C1(C)C=CC=CC=1.CCO.O.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>[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:24])[N:8]3[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:19])=[O:20])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)=[CH:35][CH:34]=1)#[N:32]
Reactant: CN(C)S(=O)(=O)c1ccc(CN2C(=O)Cc3ccc(Br)cc32)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)Cc3ccc(-c4ccc(C#N)cc4)cc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
4-(6-Bromo-2-oxo-2,3-dihydro-indol-1-ylmethyl)-N,N-dimethyl-benzenesulfonamide (1.60 g, 4.24 mmol) and tetrakis(triphenylphosphine)palladium (0) (195 mg, 0.17 mmol) were dissolved in a solution of 25 ml of toluene and 4 ml of EtOH under an atmosphere of dry N2. To the reaction mixture was added a solution of aqueous sodium carbonate (Na2CO3) (1.03 g, 9.75 mmol) dissolved in 6 ml of water followed by 4-cyanobenzene boronic acid (1.55 g, 10.6 mmol). The reaction mixture was heated to 100° C. and stirred at this temperature overnight. The reaction mixture was concentrated under vacuum and then partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was dried over MgSO4, filtered and concentrated under vacuum to give a brown oil. The brown oil was chromatographed on silica gel eluting with a gradient from DCM to DCM/MeOH (98:2) to give 1.15 g of the titled compound as an orange solid in 63% yield.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)CO.Cl>[Cu]I.C(OCC)C.O.CC(O)C>[C:18]1([N:9]2[CH2:16][CH2:15][CH2:14][C@H:10]2[C:11]([OH:13])=[O:12])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Ic1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)O
Product: O=C(O)[C@@H]1CCCN1c1ccccc1
Yield: 70.1 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), L-proline (138 mg, 1.20 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). After heated for a specified duration, the reaction was allowed to reach room temperature. Water and diluted HCl (10%) was added until ˜pH 3. Diethyl ether (2 mL) was added and the organic layer was analyzed by tlc. The reaction mixture was further extracted by diethyl ether (4×10 mL) and the combined organic phase was washed with brine and dried over Na2SO4. The solvent was rotary evaporated and the yellowish-brown residue was purified by column chromatography using a solvent mixture (diethyl ether/ethyl acetate=1/1, Rƒ=0.2) to afford N-phenyl-L-proline (134 mg, 70% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and indicated >95% purity. See Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459-12467.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:31][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(S(C)(=O)=O)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(S(C)(=O)=O)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)piperidine-1-carboxylate (505 mg, 1.23 mmol) (from example 38, step 1) was suspended in MeOH (5 mL) and cooled to −40° C. 3.8 M sodium hydroxide (0.323 mL, 1.23 mmol) in water was added. After 20 min, hydroxylamine (50% in water, 0.075 mL, 1.23 mmol) was added and stirring continued at −40° C. for 3 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (6.14 mL, 36.82 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 15-40% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 25 minutes with a flow of 19 mL/min. Trans-methyl 2-(4-(methylsulfonyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (301 mg, 64.5%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.61-1.73 (m, 1H), 1.91-1.99 (m, 1H), 2.05-2.14 (m, 1H), 2.66-2.82 (m, 2H), 2.91 (t, 1H), 3.05 (s, 3H), 3.77 (s, 3H), 4.12-4.46 (m, 1H), 5.60-5.80 (m, 2H), 7.44 (d, 2H), 7.95 (d, 2H). MS m/z 381 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13]C(=O)[NH:11][CH:10]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[NH2:11][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=1)[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[OH:13]
Reactant: COc1ccc(C2OC(=O)NC2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(O)C(N)Cc2ccc(C(F)(F)F)cc2)cc1
Yield: 90.7 %

Procedure:
To a solution of (4RS,5SR)-5-(4-methoxyphenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (7.0 g, 19.9 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (12.45 ml, 99.6 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (300 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (5.87 g, 91%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH2:9][F:10])[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([Br:32])[CH2:9][F:10])[N:7]=1
Reactant: OC(CF)c1cccc(Br)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FCC(Br)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(6-Bromopyridin-2-yl)-2-fluoroethanol (0.525 g, 2.39 mmol) and triphenylphosphine (1.252 g, 4.77 mmol) were taken up in DCM (25 mL). A solution of carbon tetrabromide (1.582 g, 4.77 mmol) in DCM (10 mL) was added and the resulting mixture stirred at room temperature overnight. The precipitate was removed by filtration and the filtrate concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-10% EtOAc-hexanes) gave the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=2[N:7]=1.[OH:26][CH2:27][CH2:28][NH2:29]>>[OH:26][CH2:27][CH2:28][NH:29][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:6]=2[N:7]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCCCCCO)ncnc23)CC1
Reactant: NCCO
Product: O=S1CCN(c2nc(NCCO)nc3c(NCCCCCO)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-(5-hydroxypentyl-amino)-4-(1-oxidothiomorpholino)-pyrimido[5,4-d]pyrimidine (melting point: 202°-204° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[NH:7][CH:6]=1)=[O:4].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[N:31]=1>O1CCOCC1.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>[CH3:28][C:2]([CH3:1])([CH3:27])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:31]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: Brc1cccc(N2CCCC2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(N4CCCC4)n3)nc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 1.9 %

Procedure:
A mixture of 2,2-dimethyl-1-(2-tributylstannanyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-propan-1-one (115 mg, 0.23 mmol), 2-bromo-6-pyrrolidin-1-yl-pyridine (53 mg, 0.23 mmol), and Pd(PPh3)4 (27 mg, 0.023 mmol) in dioxane (1 mL) was stirred at 140° C. in a microwave for 1 h. The resulting mixture was treated with additional Pd(PPh3)4 (27 mg, 0.023 mmol), stirred at 150° C. in a microwave for 30 min, and concentrated. The crude product was purified by flash chromatography using 4 g of silica gel and EtOAc in hexanes as eluant, 3 consecutive purifications by preparative thin layer chromatography using 2:1 hexanes:EtOAc as eluant, and a recrystallization from CH2Cl2 and ethyl ether to provide 1.5 mg of 2,2-dimethyl-1-[2-(6-pyrrolidin-1-yl-pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a yellow powder. M+H 350.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[C:5]1=[O:14].C(O[Cl:20])(C)(C)C>CO>[Cl:20][N:7]1[C:8]([CH3:10])([CH3:11])[CH2:9][N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:14])[C:6]1([CH3:13])[CH3:12]
Reactant: CC(C)(C)OCl
Reactant: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Solvent: CO
Product: CC1(C)CN(CCO)C(=O)C(C)(C)N1Cl
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 1-(2-hydroxyethyl)-3,3,5,5-tetramethylpiperazin-2-one (125 mg, 0.63 mmol) in methanol (1 ml) was cooled to 0° C. tert-Butylhypochlorite (106 ul, 0.94 mmol) was added. The resulting solution was stirred for 60 minutes, and then concentrated under reduced pressure. The crude material was purified by column chromatography eluting from silica gel with a gradient of 0-8% methanol in dichloromethane to give 111 mg of a white solid. 1H NMR (D2O, 400 MHz) δ 1.21 (s, 3H), 1.43 (s, 3H), 3.36 (s, 2H), 3.43-3.345 (t, J=5.6 Hz, 2H), 3.64-3.66 (t, J=5.6 Hz, 2H). 13C NMR (D2O, 100 MHz) δ 172.9, 68.1, 60.0, 58.4, 57.4, 49.6, 25.5, 22.7. LRMS (ESI/APCI) m/z 235 [M+H]+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:11][C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:8]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:29])(=O)=O)=CC=1.O>C1COCC1>[F:29][C:7]1[S:11][C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[N:9][CH:8]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=C(Nc1ncc(Br)s1)C(F)(F)F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ncc(F)s1)C(F)(F)F
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
NEt3 (63.4 mL, 455 mmol) was added to a stirred suspension of 5-bromothiazol-2-ylamine hydrobromide (102.7 g, 379 mmol) in CH2Cl2 (1.5 L). After 1 h, TFAA (64.2 mL, 455 mmol) was added dropwise at 0° C. over 15 min. The mixture was allowed to warm to 20° C. over 1 h, before being stirred for an additional 2 h. H2O (600 mL) was added and the resulting precipitate was collected. The aqueous layer of the filtrate was separated and extracted with CHCl3 (3×300 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The collected precipitate and residual solid were combined and triturated with EtOAc-n-C6H14 to give N-(5-bromothiazol-2-yl)-2,2,2-trifluoroacetamide: δH (CDCl3): 7.45 (1H, s), 13.05 (1H, br). n-BuLi (253 mL of a 1.58M solution in hexanes, 403 mmol) was added dropwise over 50 min to a stirred solution of the above amide (50.0 g, 183 mmol) in anhydrous THF (1.3 L) at −78° C. After 1.5 h, a solution of N-fluorobenzenesulphonimide (86.0 g, 275 mmol) in anhydrous THF (250 mL) was added dropwise over 30 min. The mixture was stirred for 3 h, before being warmed up to −30° C. H2O (300 mL) was added and the mixture was filtered through a Celite pad. The solid collected and Celite were washed with Et2O (400 mL) and H2O (400 mL). The organic layer of the filtrate was separated and extracted with water (2×400 mL). The combined aqueous layers were washed with Et2O (400 mL), before being acidified to pH 6.5 with 2M HCl and extracted with EtOAc (2×400 mL). The combined organic extracts were washed with H2O (2×400 mL) and brine, before being dried (MgSO4), filtered and concentrated. Column chromatography (EtOAc-n-C6H14, 1:3 to 1:2) gave N-(5-fluorothiazol-2-yl)-2,2,2-trifluoroacetamide: δH (CDCl3): 7.13 (1H, d). AcCl (12.6 mL, 175 mmol) was added dropwise to a stirred solution of this amide (15.7 g, 73 mmol) in MeOH (300 mL) at 0° C. The mixture was stirred at 20° C. for 30 min, heated under reflux for 1 h, and finally concentrated in vacuo. The residual solid was triturated with THF to give the title compound: δH (D2O): 7.00 (1H, d).
Reaction SMILES: [C:1]1([S:7]([C:10]2[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[C:1]1([S:7]([C:10]2[S:14][C:13]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)c2ccccc2)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(S(=O)(=O)c2ccccc2)s1
Yield: 40 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with 5-benzenesulfonyl-thiophene-2-sulfonyl chloride (17.7 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 40% yield (8.9 mg). MS (ESI+) calcd mass for C17H13N5O4S3 447.012966, found 447.013676.