Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1nccnc1Cl)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
To a suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (900 mg, 5 mmol) in dichloromethane (25 mL) is added 4-fluorobenzoyl chloride (730 μL, 6.1 mmol) followed by DIPEA (2.0 mL, 11 mmol). After 1 day, the mixture is concentrated and diluted with saturated aqueous ammonium chloride and extracted with EtOAc (3×40 mL). The combined organic layers are washed with brine (3×25 mL), dried over magnesium sulfate, filtered and concentrated. The residue is passed through a pad of silica gel using dichloromethane-heptane (1:1) to load the sample and then eluting with dichloromethane to afford N-(3-chloro-pyrazin-2-ylmethyl)-4-fluoro-benzamide as an oil which partially solidified.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[N:18]#[C:19][NH2:20].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:19](=[NH:18])([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:14][CH:13]=1)[NH2:20]
Reactant: Cc1cccc(Oc2ccc(CCO)cc2)n1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cccc(Oc2ccc(CCOC(=N)N)cc2)n1
Temperature: 55 °C
Yield: 49.1 %

Procedure:
To a solution of 2-{4-[(6-methyl-2-pyridinyl)oxy]phenyl}ethanol (1.7 g, 7.41 mmol) and cyanamide (0.405 g, 9.64 mmol) in dry THF (20 mL) under nitrogen was added triflic acid (0.856 mL, 9.64 mmol). The mixture was heated at 55° C. for 4 h. Purification via reverse phase flash chromatography afforded the title compound (1.4 g, 3.64 mmol, 49.1% yield) as a colorless oil. LCMS: rt=1.87 min, [M+H]=272
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5](C(SCC(C)C(Cl)=O)=O)=[CH:4][C:3]=1S(=O)(=O)N.[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](O)=O.[C:29](=O)([O-])[O-].[K+].[K+]>CCOCC>[CH:28]1([NH:21][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:15][CH2:16]2)[CH2:27][CH2:26][CH2:22][CH2:23][CH2:29]1
Reactant: CC(CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
A solution of 4.2 g of 3-(4-chloro-3-sulfamoylbenzoylthio)-2-methylpropionyl chloride in 15 ml ofether is added dropwise to a mixture of 1.6 g of L-proline, aqueous 1 N potassium carbonate solution and 20 ml of ether under ice-cooling and stirring, and the resulting mixture is stirred at room temperature for 2 hours. The aqueous layer is then collected and acidic with dilute hydrochloric acid, and the separated oil is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in acetonitrile and 2 g of dicylohexylamine is added. The oil thus obtained is washed several times with acetonitrile by decantation. The resulting crystals are recrystallized from isopropanol to give dicylohexylamine saltof 1-[3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionyl]-L-proline as white crystalline powder, melting at 143°-146° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>CN(C=O)C>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: COC(=O)CO
Reactant: NS(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(S(N)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 32 %

Procedure:
To a stirred suspension of NaH (2.8 g, 0.07 mol, 50% in mineral oil) in DMF (50 mL) is added dropwise methyl glycolate (5.5 g, 0.06 mol) over a period of 10 min. The mixture is heated up to 50° C. for 3 h and cooled down to room temperature. 4-Fluorobenzenesulfonamide g, 0.0114 mol) is added portionwise. After stirring at 50° C. for 10 h, the reaction mixture is cooled down and poured into ice-water containing HCl. The product is extracted with DCM (2×100 mL). The combined organic phase is washed with water and dried over Na2SO4. The solvent is evaporated under reduced pressure and the residue is purified by chromatography (silica gel, 60-120 mesh) with chloroform/methanol (9/1) as eluent to afford 900 mg (32%) of the title compound as a solid. 1H NMR (CDCl3, 400 MHz) δ 7.68-721 (m, 2H), 7.10-7.12 (m, 2H), 6.45 (br s, 2H), 4.51 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: COc1ccc(O)c(Br)c1
Product: COc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-methoxy-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: NCCC[Si:5](OC)(OC)OC.C(OCC)(=O)/C=C\C(OCC)=O.C([O:26][C:27](=[O:46])[C@H:28]([CH2:40][C:41]([O:43]CC)=[O:42])[NH:29]CCC[Si](OC)(OC)OC)C>>[NH2:29][C@H:28]([C:27]([OH:46])=[O:26])[CH2:40][C:41]([OH:43])=[O:42].[SiH4:5]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CCOC(=O)C[C@H](NCCC[Si](OC)(OC)OC)C(=O)OCC
Agent: CCOC(=O)/C=C\C(=O)OCC
Product: N[C@@H](CC(=O)O)C(=O)O
Product: [SiH4]
Temperature: 25 °C

Procedure:
1482 parts (8.27 equiv.) of 3-aminopropyltrimethoxysilane were added to a 5 liter flask fitted with agitator, thermocouple, nitrogen inlet and addition funnel with condenser. 1423.2 parts (8.27 equiv.) of diethyl maleate were added dropwise through the addition funnel over a period of 2 hours. The temperature of the reactor was maintained at 25° C. during the addition. The reactor was maintained at 25° C. for an additional 5 hours at which time the product was poured into glass containers and sealed under a blanket of nitrogen. After one week the unsaturation number was 0.6 indicating the reaction was ˜99% complete. The product, N-(3-trimethoxysilyipropyl) aspartic acid diethyl ester, had a viscosity of 11 mPa.s at 25° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].O.Cl.Cl.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[NH:19][C:20](=[O:28])[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[NH:19][C:20]([CH2:21][N:22]1[CH2:23][CH2:24][N:25]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:26][CH2:27]1)=[O:28]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN1CCN(CC(=O)Nc2c(C)cccc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
Ethyl bromoacetate (12.12 g, 0.073 mol) in dry acetonitrile (30 mL) was added dropwise to a mixture of N-(2,6-dimethylphenyl)-1-piperazineacetamide dihydrochloride hydrate (18.0 g, 0.073 mol) and potassium carbonate (18.0 g, 0.13 mol) in dry acetonitrile (200 mL). The mixture was stirred at room temperature for 16 h before it was filtered and evaporated. The residue was partitioned between ethyl acetate and water and the organic phase was separated, washed with brine dried and concentrated. There was isolated 21 g (86%) of the XI compound as a colorless oil which was used without further purification; 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.06 (s, 3H), 4.11 (q, J=3.6 Hz, 2H), 3.22 (s, 2H), 3.13 (s, 2H), 2.68 (br s, 8H), 2.14 (s, 6H), 1.19 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 171.65 (0), 169.63 (0), 166.02 (0), 136.72 (0), 136.67 (0), 129.36 (+), 128.09 (+), 63.07 (-), 61.54 (-), 60.24 (-), 54.67 (-), 53.59 (-), 19.7 (+), 15.88 (+); IR (KBr) 3242, 3020, 2988, 2964, 2936, 2914, 2878, 2824, 1744, 1662, 1530, 1478, 1466, 1444, 1428, 1390, 1380, 1306, 1278, 1224, 1198, 1166, 1136, 1042, 1020, 836, 762, 718 cm-1 ; MS (DCI) m/e 334.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)CCC.[N+:22]([CH2:25][CH2:26][CH3:27])([O-:24])=[O:23]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:25]([N+:22]([O-:24])=[O:23])[CH2:26][CH3:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Solvent: CCCCN
Product: CCC(=Cc1ccc(OCc2ccccc2)cc1)[N+](=O)[O-]
Reaction time: 3 h

Procedure:
The starting material is prepared as follows: The mixture of 80 g of p-benzyloxybenzaldehyde, 100 ml of 1-nitro-propane and 5 ml of n-butylamine is placed in a reflux extractor filled with molecular sieves (type 5A), and refluxed for four hours. It is evaporated, the residue dissolved in diethyl ether containing some ethyl acetate and the solution stirred vigorously with a saturated sodium bisulphite solution for three hours. The inorganic layer is washed with ethyl acetate and the combined organic extracts washed with brine, dried and evaporated to afford the 1-(4-benzyloxyphenyl)-2-nitro-1-butene, which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:21][C:22]1([CH3:29])[O:26][CH:25]([CH2:27][NH2:28])[CH2:24][O:23]1>CO.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:28][CH2:27][CH:25]2[CH2:24][O:23][C:22]([CH3:29])([CH3:21])[O:26]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC1(C)OCC(CN)O1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(Cl)nc(NCC3COC(C)(C)O3)c2c1
Yield: 100 %

Procedure:
A solution of 2,4-dichloro-6-methylquinazoline (300.0 mg, 1.4 mmol), triethylamine (0.5 mL) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (0.2 mL, 1.5 mmol) in methanol (2.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 431 mg of the crude product as a white solid. MS obsd. (ESI+) [(M+H)+] 308.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[CH:26]=[CH:25][C:17]3[NH:18][CH2:19][CH2:20][NH:21][S:22](=[O:24])(=[O:23])[C:16]=3[CH:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.Cl.O1CCOCC1.[Pd]>[O:24]=[S:22]1(=[O:23])[C:16]2[CH:15]=[C:14]([O:13][C:12]3[CH:27]=[CH:28][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:26]=[CH:25][C:17]=2[NH:18][CH2:19][CH2:20][NH:21]1
Reactant: O=S1(=O)NCCNc2ccc(Oc3ccc(OCc4ccccc4)cc3)cc21
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=S1(=O)NCCNc2ccc(Oc3ccc(O)cc3)cc21

Procedure:
The product of Example 8 (0.76 mmol) is hydrogenated for 1 hour at atmospheric pressure in 60 ml of ethanol in the presence of 30 mg of 10% palladium-on-carbon and 2 drops of 4N HCl solution in dioxane. The catalyst is removed by filtration and the filtrate is evaporated to dryness. The residue is taken up in the hot state in ethyl acetate. The organic phase is washed with 1% NaHCO3 solution and then with saturated NaCl solution, dried (MgSO4), filtered and evaporated. The residue is triturated in a mixture of ethyl acetate/ethyl ether to yield, after filtration, the title product.
Reaction SMILES: [F:1][CH:2]([F:28])[S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)OC(C)(C)C)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].ClCCl>ClCCCl>[F:29][C:30]([F:35])([F:34])[C:31]([O-:33])=[O:32].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([S:3][CH:2]([F:28])[F:1])=[CH:5][CH:6]=2)=[O:27])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)Nc2ccc(SC(F)F)cc2)cc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CC(=O)Nc2ccc(SC(F)F)cc2)cc1
Product: O=C([O-])C(F)(F)F

Procedure:
Tert-butyl 4-[2-({4-[(difluoromethyl)thio]phenyl}amino)-2-oxoethyl]phenylcarbamate (Example 27) (3.63 g) was stirred in 25% trifluoroacetic acid/dichloromethane at room temperature for 45 minutes. The mixture was diluted with 1,2-dichloroethane (25 mL) and evaporated down twice. The residue was recrystallized from ethyl acetate (15 mL) and hexane (15 mL). The product was obtained as the 1:1 trifluoroacetate salt, 2-(4-aminophenyl)-N-(4-(difluoromethylthio)phenyl)acetamide 2,2,2-trifluoroacetate: 1H NMR (300 MHz, DMSO-d6) δ ppm 3.45-4.13 (m, 2H) 3.62 (s, 2H) 7.03 (d, J=8.5 Hz, 2H) 7.38 (t, J=56.1 Hz, 1H) 7.28 (d, J=8.5 Hz, 2H) 7.47-7.55 (m, 2H) 7.64-7.72 (m, 2H) 10.36 (s, 1H) MS (DCI/NH3) m/z 309.0 (M+H)+; Anal. C15H14F2N2OS C2HF3O2: C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH3:28])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of trans-methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate (3 g, 6.81 mmol) in acetonitrile (40 mL), cesium carbonate (4.4 g, 13.62 mmol) and methyl iodide (4.83 g, 34.05 mmol) were added; the resulting reaction mixture was heated at 80° C. for 7 h. Upon completion, the reaction mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and filtrate was concentrated to afford desired crude compound which then purified by column chromatography giving the desired compound (1.3 g, 43%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>CO>[C:24]([N:4]([CH2:5][CH2:6][OH:7])[CH2:3][CH2:2][NH:1][C:10](=[O:11])[C:9]([F:16])([F:15])[F:8])(=[O:26])[CH3:25]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)Cl
Reactant: NCCNCCO
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N(CCO)CCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(2-aminoethylamino)ethanol (1.15 g, 11 mmol, 1.10 equiv) in 50 mL MeOH at 0° C. was slowly added ethyl trifluoroacetate (1.42 g, 10 mmol, 1.00 equiv). The mixture was stirred at room temperature for 5 hours. Solvents were then removed, and the residue was dissolved in 50 mL methylene chloride. Triethylamine (1.52 g, 15 mmol) was added followed by acetyl chloride (0.94 g, 12 mmol, 1.20 equiv). Removal of solvent yielded N-acetyl-N-(2-trifluoroacetylaminoethyl)-(2′-hydroxyethyl)amine (crude) as a white solid. This crude product was subjected to a series of reactions similar to those for SBR-11-4416. 0.60 g final product was isolated as a white solid after HPLC purification. 1H NMR (CDCl3, ppm): 8.47(d, 2H), 7.99 (brs, 2H), 7.14-7.35 (m, 10H), 5.20 (s, 1H), 2.96-3.56 (m, 12H), 2.18 (s, 3H). MS: 482.24 (calc'd); 483.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20](I)=[N:19]3)[C@@H:12]([CH3:29])[CH2:11]2)=[C:4]([F:30])[CH:3]=1.[C:31]([Cu])#[N:32].CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:31]#[N:32])=[N:19]3)[C@@H:12]([CH3:29])[CH2:11]2)=[C:4]([F:30])[CH:3]=1
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 175 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
A mixture of 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (2.2 g, 4.0 Mmol, 1 eq), CuCN (3.6 g, 40 Mmol, 10 eq), and DMF (25 mL) was stirred at 175° C. for 1 hrs. The reaction mixture was cooled to rt, diluted with ethyl acetate and filtered. The filtrate was washed with water, dried over Na2SO4, and purified by flash chromatography to provide 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.6 g).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].N1CCCCC1.[CH:14]1([NH:17][C:18]2[N:23]3[N:24]=[CH:25][C:26]([CH:27]=O)=[C:22]3[N:21]=[C:20]([NH:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=3)[CH:19]=2)[CH2:16][CH2:15]1>C(O)C.O>[CH:14]1([NH:17][C:18]2[N:23]3[N:24]=[CH:25][C:26](/[CH:27]=[C:7]4/[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]/4)=[C:22]3[N:21]=[C:20]([NH:29][C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=3)[CH:19]=2)[CH2:15][CH2:16]1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Nc3cc(F)cc(F)c3)nc12
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(Nc4cc(F)cc(F)c4)nc23)N1
Temperature: 80 °C
Reaction time: 12 h
Yield: 27.3 %

Procedure:
Hydantoin (28 mg, 0.28 mmol) and piperidine (42 μL, 0.42 mmol) were added to 7-(cyclopropylamino)-5-(3,5-difluorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (52 mg, 0.16 mmol) dissolved in ethanol (1 mL). The reaction was heated at 80° C. After 12 h, the reaction was cooled to r.t., diluted with water (2 mL), and the precipitate was collected and washed with 1:1 ethanol:water (5 mL). The solid was dried in vacuo to give (Z)-5-((7-(cyclopropylamino)-5-(3,5-difluorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (18 mg, 28% over 3 steps). LCMS (M+1=440)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:13]([C:15](=[C:20]1[CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]>C1COCC1.[Cu](I)I>[C:13]([CH:15]([C:20]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:29][C:24]2([CH2:25][CH2:26][CH2:27][CH2:28]2)[O:23][CH2:22][CH2:21]1)[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: COC(=O)C(C#N)=C1CCOC2(CCCC2)C1
Reactant: Brc1ccccn1
Agent: I[Cu]I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C1(c2ccccn2)CCOC2(CCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A solution of 2-bromopyridine (14.4 ml, 150 mmo) in THF (75 ml) was added dropwise to a solution of isopropylmagnesium chloride (75 ml, 2M in THF) at 0° C. under N2, the mixture was then stirred at rt for 3 h, copper Iodide (2.59 g, 13.6 mmol) was added and allowed to stir at rt for another 30 min before a solution of a mixture of E and Z isomers of methyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (16 g, 150 mmol) in THF (60 ml) was added in 30 min. The mixture was then stirred at rt for 18 h. The reaction mixture was poured into a 200 g ice/2 N HCl (100 ml) mixture. The product was extracted with Et2O (3×300 ml), washed with brine (200 ml), dried (Na2SO4) and concentrated. The residual was purified by flash chromatography (100 g silica gel column, eluted by EtOAc in hexane: 3% 2 CV; 3-25%, 12 CV; 25-40% 6 CV gave methyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.44 g, 72% yield, m/z 315.0 [M+H]+ observed) as an amber oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=1>>[CH3:42][C:40]1[CH:41]=[C:36]([C:17]2[CH:16]=[CH:15][C:14]([C@@H:12]([N:8]3[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][OH:1])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:10][C:9]3=[O:11])[CH3:13])=[CH:19][CH:18]=2)[CH:37]=[C:38]([CH3:43])[N:39]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)n1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.228, m/z=445; 1H NMR (CDCl3) 1.32 (m, 1H) 1.51 (d, 3H), 1.60-1.72 (m, 1H), 1.86-2.02 (m, 2H), 2.19 (m, 1H), 2.25-2.39 (m, 2H), 2.79 (s, 6H), 2.93 (m, 1H), 3.50 (t, 2H), 5.64 (m, 1H), 7.00 (d, 2H), 7.21 (m, 2H), 7.29 (m, 2H), 7.32 (m, 3H), 7.40 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.C[O-].[Na+].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>CO.CN(C)C=O>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][O:13][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([NH2:2])=[CH:12]2)=[CH:7][CH:8]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Nc1ccc2ccc(O)cc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: Nc1ccc2ccc(OCc3ccc4ccccc4n3)cc2c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a suspension of 40.0 g 7-amino-2-naphthol hydrochloride (205 mmol) in 250 mL methanol under nitrogen is added 451 mL of 0.91N sodium methoxide (410 mmol) in methanol. After 1 hour of stirring, the solvent is removed and the residue is taken up in 500 mL dimethylformamide and cooled to 10° C. under nitrogen. A solution of 36.3 g 2-(chloromethyl)quinoline (205 mmol) in 200 mL dimethylformamide is added. After stirring overnight at ambient temperature, the reaction is stripped of solvent, water is added and the precipitate is filtered off, dried and recrystallized from toluene to afford 31.1 g (62%) of white crystals, which is further purified by filtration through Florisil. Recrystallization from toluene affords white crystals, m.p. 164.5°-166.0° C.
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>C1COCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[NH2:1][C:2]1[C:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][OH:15])=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[NH2:1][C:2]1[C:12]([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][OH:15])=[CH:18][CH:19]=2)=[CH:11][C:10]([C:12]2[CH:11]=[CH:10][C:4]([CH2:5][OH:6])=[CH:3][CH:2]=2)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Nc1c(I)cc(Br)c2c1C(=O)NC2=O
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1CCOC1
Product: Nc1c(-c2ccc(CO)cc2)cc(-c2ccc(CO)cc2)c2c1C(=O)NC2=O
Product: Nc1c(-c2ccccc2CO)cc(Br)c2c1C(=O)NC2=O
Yield: 29 %
Yield: 64 %

Procedure:
In a similar manner to Step 2 of Example 2, 3-amino-4-iodo-6-bromophthalimide (100 mg, 0.273 mmol) was dissolved in THF (7 mL), and the solution was treated with 4-hydroxymethylphenylboronic acid (83 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol) and copper(I)thiophene-2-carboxylate (104 mg, 0.546 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=15/1) to obtain 3-amino-4-(hydroxymethylphenyl)-6-bromophthalimide (61 mg, yield 64%) and 3-amino-4,6-di(4-hydroxymethylphenyl)phthalimide (29 mg, yield 29%).