Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:31]#[C:30][CH2:29][OH:32])=[CH:4][C:3]=1[CH3:9]
Reactant: C#CCO
Reactant: Cc1cc(I)ccc1Cl
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C#CCO)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-5-iodotoluene (5.00 g), copper(I) iodide (75.4 mg), triphenylphosphine (260 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (410 mg), propargyl alcohol (1.29 ml), diisopropylethylamine (13.8 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 8 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.08 g) as a brown solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]=[CH:18][CH2:19]Br>C(COC)OC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH2:19][CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10](=[O:12])[CH3:11])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: Clc1cccc(C=CCBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1cccc(Cl)c1)c1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (25.20 g., 0.60 mole, oil dispersion) is suspended in glyme (800 ml.) and phenyl acetone (80.50 g., 0.60 mole) in glyme (100 ml.) is added dropwise with stirring. After complete addition the mixture is heated to reflux for one hour. The mixture is cooled to room temperature and a solution of crude m-chlorocinnamyl bromide (139 g., 0.6 mole) in glyme (100 ml.) is added dropwise. When addition is complete the mixture is refluxed for 24 hours then allowed to cool. After filtration of inorganic salts and removal of solvent from the filtrate, vacuum distillation provides 36.11 g., b.p. 158.5°-163°/0.1 mm.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([Cl:18])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(3-(trifluoromethyl)phenyl)acetic acid (4.78 g, 23.4 mmol) in DCM (46 mL) was added oxalyl chloride (12.9 mL, 25.8 mmol). One drop of DMF was then added and the mixture was stirred for 1.5 hours at room temperature. The mixture was concentrated to afford the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:20]2[N:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31]C)=[O:30])=[CH:22][N:21]=2)[CH:4]=1.C[Si](C)(C)[O-:38].[K+].OO>C1COCC1.O.C(O)(=O)C>[CH3:1][S:2]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][CH:10]=2)[N:5]([C:20]2[N:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([OH:31])=[O:30])=[CH:22][N:21]=2)[CH:4]=1)=[O:38]
Reactant: COC(=O)c1cccc(-c2cnc(-n3cc(SC)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Reactant: C[Si](C)(C)[O-]
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1cn(-c2ncc(-c3cccc(C(=O)O)c3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Prepared from methyl 3-(2-(3-(methylthio)-6-(morpholine-4-carbonyl)-1H-indol-1-yl)pyrimidin-5-yl)benzoate (precursor of example 192) in two reaction steps comprising an ester hydrolysis with potassium trimethylsilanolate in THF and water and an oxidation of the thioether with hydrogen peroxide in acetic acid. White solid. Yield: 90 mg. Melting range: 230-235° C.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5].[Br:23]N1C(=O)CCC1=O>C(Cl)Cl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Product: CCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-{[(1S)-1-Methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1050 g) was dissolved in DCM (10.5 L) to give a yellow/orange solution which was cooled to 0° C. N-Bromosuccinimide (922 g, 1.5 eq) was charged in 3 equal portions 20 mins. apart and the resultant reaction mixture was stirred at 0-5° C. for 4 hours. The reaction was then quenched by addition of a solution of 500 g sodium thiosulfate pentahydrate in 5.0 L water. The resultant biphase was mixed thoroughly at 20° C. and then the phases were separated. The organics were washed again with a solution of 500 g sodium thiosulfate pentahydrate in 5.0 L water then 500 g dipotassium phosphate in 5.0 L water and finally with 5.0 L water. The organic phase was dried over magnesium sulfate (822 g) and evaporated on a rotary evaporator until foaming became prohibitive. The mixture was then solvent-exchanged into methanol by repeated addition and removal of methanol until sufficient DCM had been removed (as confirmed by NMR). The product was afforded as a red/brown gum containing entrained solvent (1.28 kg corrected for solvent, 96% theoretical yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[N:22]=[C:23]=S>C(#N)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[NH:22][C:23]1[NH:1][C:2]2[CH:3]=[C:4]([OH:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=2[N:12]=1
Reactant: COC(=O)c1cc(N)c(N)cc1O
Reactant: Fc1cccc(Cl)c1N=C=S
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2cc1O
Yield: 39.6 %

Procedure:
The title compound was prepared following the procedure described for step-2 of intermediate-55 using methyl 4,5-diamino-2-hydroxybenzoate (step-1 of Intermediate-55, 0.700 g, 3.840 mmol), acetonitrile (5.0 mL), 1-chloro-3-fluoro-2-isothiocyanatobenzene (Intermediate-14, 0.700 g, 3.760 mmol) and N,N-di-isopropyl carbodimide (1.0 mL) to afford 0.5 g of the desired product. 1HNMR (DMSO-d6): δ 3.87 (s, 3H), 6.61 (s, 1H), 7.29-7.46 (m, 4H), 10.62 (s, 1H); MS [M+H]+: 336.17.
Reaction SMILES: C(OC1(CC2C3C(=CC=CC=3)NC=2)C2C(=CC=C(Cl)C=2)N(CCC)C1=O)(=O)C1C=CC=CC=1.C([O:42][CH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([CH3:52])[CH:50]=2)[N:45]([CH2:53][CH2:54][CH3:55])[C:44]1=[O:56])(=O)C1C=CC=CC=1.C(O[CH2:66][C:67]1[C:75]2[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=2)[N:69]([C:76](=[O:83])[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH:68]=1)(=O)C1C=CC=CC=1>>[C:76]([N:69]1[C:70]2[C:75](=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:67]([CH2:66][C:43]2([OH:42])[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([CH3:52])[CH:50]=3)[N:45]([CH2:53][CH2:54][CH3:55])[C:44]2=[O:56])=[CH:68]1)(=[O:83])[C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1
Reactant: O=C(OCc1cn(C(=O)c2ccccc2)c2ccccc12)c1ccccc1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Agent: CCCN1C(=O)C(Cc2c[nH]c3ccccc23)(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Product: CCCN1C(=O)C(O)(Cc2cn(C(=O)c3ccccc3)c3ccccc23)c2cc(C)ccc21

Procedure:
This compound was made in a method analogous to 3-((1H-indol-3-yl)methyl)-5-chloro-2-oxo-1-propylindolin-3-yl benzoate using 5-methyl-2-oxo-1-propylindolin-3-yl benzoate and (1-benzoyl-1H-indol-3-yl)methyl benzoate. 1H-NMR δ 8.33 (d, 1H), 7.53 (m, 2H), 7.45-7.39 (m, 4H), 7.31 (dd, 1H), 7.29 (m, 1H), 7.17 (s, 1H), 7.08 (d, 1H), 6.59 (m, 2H), 3.53 (m, 1H), 3.40 (d, 1H), 3.29 (d, 1H), 3.20 (m, 1H), 2.77 (s, OH), 2.30 (s, 3H), 1.15 (m, 2H), 0.56 (t, 3H). Calculated mass for C28H26N2O3, 438.19. Observed 461.2 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(F)c1
Reaction time: 18 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.96 g, 5.58 mmol) was diluted with THF (60 mL), treated with 3-fluoro-benzoyl chloride (0.738 mL, 6.14 mmol) and stirred for 18 h. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (1.7 g, 99%).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].C(OC(=O)C)(=O)C.[Br:26]Br>C(O)(=O)C>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([Br:26])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: BrBr
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3'-Azido-5-bromo-2',3'-dideoxyuridine was prepared from the known 3'-azido-2',3'-dideoxyuridine (T. A. Krenitsky, et al., J. Med. Chem., 26, 891, (1983)) (0.827 g, 3.3 mMol) by first acetylating the 5'-hydroxyl group with acetic anhydride (15 mL) then by brominating the 5 position by the addition of acetic acid (0.5 mL) and bromine (0.566 g). The red-brown solution was stirred at room temperature for two hours. The reaction was taken to an oil in vacuo and triturated with ethyl ether. The oil was dissolved in methanol ammonia to remove the acetyl group. The desired product was isolated by chromatography on silica gel by elution with CHCl3 :MeOH (95:5 v/v). The yield was 32%; mp=148°-149° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][C:32](=[O:34])[CH3:33])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15](/[CH:18]=[CH:19]\[CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[Na+].[Na+].[C:41]([O:44][CH:45](Br)[CH3:46])(=[O:43])[CH3:42]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[O:31][C:32](=[O:34])[CH3:33])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH:45]([O:44][C:41](=[O:43])[CH3:42])[CH3:46])=[O:26])=[C:15](/[CH:18]=[CH:19]\[CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(C)=O)c3csc(N)n3)[C@H]2SC1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC(C)=O)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of the product of Example 68 (248 mg, 0.49 mmol) in 25 ml of dry DMF was added Na2CO3 (51 mg, 0.49 mmol) and 1-acetoxyethyl bromide (82 mg, 0.49 mmol) at -10° C. The mixture was stirred at 5° C. for 30 min and 82 mg (0.49 mmol) of 1-acetoxyethyl bromide was added to the suspension. After being stirred for 30 min more, the reaction mixture was diluted with AcOEt (50 ml), washed with water (30 ml×3) and brine, dried over MgSO4 and evaporated under diminished pressure. The crude product was purified by silica gel chromatography eluted with 3% MeOH in chloroform. Removal of the solvent from appropriate eluant followed by freeze-drying gave 157 mg (54%) of the title compound, mp 125° C. (dec). IR νmax (KBr) cm-1 3430, 3290, 1770, 1680. UV λmax (pH 7 phosphate buffer) nm (ε) 228 (21900), 287 (12700). 1H NMR (DMSO-d6) δ 1.51 (3H, d, J=6 Hz, 4-COOCHCH3), 2.02 (3H, s, AcO), 2.06 (3H, s, AcO), 2.22 (3H, s, AcO), 3.47 (2H, br.s, 2-H), 4.46 (1H, q, J=6 Hz, 4-COOCHCH3), 4.55 (2H, ABq, CH2OAc), 5.12 (1H, d, J=5 Hz, 6-H), 5.70 (1H, m, 3-CH=CH), 5.95 (1H, dd, J=5 & 7 Hz, 7-H), 6.25 (1H, d, J=12 Hz, 3-CH=CH), 6.92 (1H, s, thiazole).
Reaction SMILES: [CH:1]1([C:7]2[O:11][C:10]([CH2:12][CH3:13])=[C:9]([C:14]([OH:16])=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[N:17]1([C:23]2[N:28]=[CH:27][C:26]([NH:29][C:14]([C:9]3[CH:8]=[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[O:11][C:10]=3[CH2:12][CH3:13])=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCc1oc(C2CCCCC2)cc1C(=O)O
Reactant: Nc1ccc(N2CCOCC2)nc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1oc(C2CCCCC2)cc1C(=O)Nc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
5-Cyclohexyl-2-ethyl-furan-3-carboxylic acid (26 mg, 0.116 mmol), 6-morpholin-4-yl-pyridin-3-ylamine (20 mg, 0.116 mmol), and triethylamine (49 uL, 0.348 mmol) were dissolved in 4 mL of DMF and chilled in an ice bath. To this solution was added BOP (53 mg, 0.121 mmol) in one portion. The mixture was stirred at room temperature, for one hour and then diluted with 30 mL ethyl acetate. The ethyl acetate solution was washed with saturated sodium bicarbonate (2×10 mL) and saturated sodium chloride (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness under vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexane to yield 5-cyclohexyl-2-ethyl-furan-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide as a light grey powder (11.5 mg, 26%). ES-MS calcd for C22H29N3O3 (m/e) 383.5, obsd 384 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]1([C:23]([O:25]C)=O)[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C([Mg]Cl)(C)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][C:11]2([N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13][CH2:14][CH2:15]2)[C:23]1=[O:25]
Reactant: COC(=O)C1(CCNc2ccccc2Cl)CCCN1C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC12CCN(c1ccccc1Cl)C2=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1-tert-Butyl 2-methyl 2-{2-[(2-chlorophenyl)amino]ethyl}pyrrolidine-1,2-dicarboxylate, was dissolved in anhydrous THF (4 mL) and cooled to 0° C. To this cooled solution was added isopropylmagnesium chloride in THF (2.0 M, 2 mL). The reaction vial was then sealed and heated to 64° C. and stirred for 18 h. The reaction mixture was then diluted with EtOAc and quenched by the addition of water. The crude mixture was filtered through a pad of diatomaceous earth and the filter pad was washed several times with EtOAc. The organic and aqueous layers of the filtrate were separated. The aqueous phase was extracted with EtOAc (3×10 mL) and the combined organic phases were washed with brine (2×5 mL), then dried (NaSO4), filtered, and concentrated in vacuo to afford the desired product. LC-MS: 251.1 (M−Boc+2H)+ and 295.1 (M−t-Bu+2H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:50]=[CH:51][CH:52]=2)[CH2:35][NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[C:34]([CH:50]=[CH:51][CH:52]=3)[CH2:35][NH:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H]1CCCN1c1cccc(Nc2nc(Cl)nc3scnc23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)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: C1COCCO1
Solvent: O
Product: C[C@H]1CCCN1c1cccc(Nc2nc(-c3cccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)c3)nc3scnc23)c1

Procedure:
To a solution of (S)-5-chloro-N-(3-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.58 mmol) and crude tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylamino)piperidine-1-carboxylate in 10 mL of 1,4-dioxane and 2 mL of water was added Na2CO3 (184 mg, 1.74 mmol) followed by Pd(PPh3)4 (184 mg, 0.03 mmol) under nitrogen with stirring. The mixture was refluxed for 15 hours under nitrogen. After cooled, the solvent was evaporated by rotary evaporation under reduced pressure. The residue was poured into water and extracted with EtOAc (3×15 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography (silica gel, eluting with EtOAc) to give (S)-tert-butyl 4-(3-(7-(3-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzylamino)piperidine-1-carboxylate (110 mg, 32% for the two steps). LC-MS: 250.6 [M/2+H]+, 600 [M+H]+, tR=1.57 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12](O)=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4].P(Cl)(Cl)([Cl:23])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12]([Cl:23])=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19][CH3:20])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(OC)c2oc3ccnc(O)c3c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(OC)c2oc3ccnc(Cl)c3c12

Procedure:
A solution of Methyl-1-hydroxy-6-Methoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (from step 10) (1.1 g) and phosphorous oxychloride (25 mL) was refluxed for 15-16 hours. Excess of phosphorous oxychloride was removed under vacuo. The residue obtained was diluted with water (10.0 mL) and made alkaline with solid sodium carbonate. The solid separated was filtered, washed with water and dried to get crude intermediate-12 (1.0 g) as brown solid. Purification by silica gel column using chloroform: ethyl acetate (9:1) as an eluent gave pure intermediate-12 (350 mg) as light yellow solid
Reaction SMILES: BrC(Br)C.[Mg].Br[C:7]1[C:12]2[O:13][C:14]([CH3:18])([CH3:17])[O:15][CH2:16][C:11]=2[CH:10]=[C:9]([Cl:19])[CH:8]=1.[C:20]1([C:26]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:27]2[CH:31]=[C:30]([CH:32]=[O:33])[N:29]=[CH:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.O>[Cl:19][C:9]1[CH:8]=[C:7]([CH:32]([C:30]2[N:29]=[CH:28][N:27]([C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:31]=2)[OH:33])[C:12]2[O:13][C:14]([CH3:18])([CH3:17])[O:15][CH2:16][C:11]=2[CH:10]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC1(C)OCc2cc(Cl)cc(Br)c2O1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OCc2cc(Cl)cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2O1
Temperature: 30 °C
Reaction time: 2.5 h

Procedure:
2 ml of dibromoethane are added to a suspension of 26.73 g (1 mole+10% excess) of magnesium in 250 ml of anhydrous tetrahydrofuran and warmed to about 30° C. to initiate the reaction. Immediately thereafter, 277.5 g (1 mole) of 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin dissolved in 250 ml of tetrahydrofuran are added dropwise thereto in such a manner that the temperature does not exceed 40° C. The addition takes about 150 minutes. The organomagnesium compound is cooled to about 10° C. (partial precipitation) and it is then added to a solution of 338 g (1 mole) of 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde in 2.8 liters of tetrahydrofuran which has previously been cooled to 0° C. During the addition, the temperature of the mixture increases progressively to 20° C. Stirring is continued for 1 hour at this temperature and then 53.5 g (1 mole) of ammonium chloride are added. After stirring for 1 hour, 18 ml of water are added and stirring is maintained for a further hour. The tetrahydrofuran is removed under reduced pressure. The residue is taken up in 5 liters of dichloromethane and washed with 2 liters of water containing 30 g of sodium bisulfite. The aqueous phase is separated and washed with 1 liter of dichloromethane. The organic phases are again washed with water, then dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue is recrystallized from about 4 liters of toluene at 80° C. and filtered hot on Norit. 335.6 g of alpha-(6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)-1-triphenylmethyl-1H-imidazole-4-methanol, which contans one molecule of toluene, are thus obtained. M.P.: 120° C. followed by 188° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([NH:15][CH2:16][CH2:17][F:18])=[O:14])=[O:4]>[Ni]>[CH3:22][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([NH:15][CH2:16][CH2:17][F:18])=[O:14])=[O:4]
Reactant: CN(C)C(=O)CCCC#Cc1cccc(C(=O)NCCF)c1
Agent: [Ni]
Product: CN(C)C(=O)CCCC=Cc1cccc(C(=O)NCCF)c1
Yield: 40 %

Procedure:
Hydrogenation of 3-(5-dimethylcarbamoyl-pent-1-ynyl)-N-(2-fluoro-ethyl)benzamide (26)(0.040 g, 0.13 mmol) using BER/Ni catalyst gave 40% 28, and 55% of starting material. The mixture was separated by reverse-phase HPLC chromatography (30% acetonitrile/70% water 20 min isocratic program) to give 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-fluoro-ethyl)-benzamide 28 (5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl.[Cl-].[NH4+]>[Br:24][C:16]1[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:14][N:5]2[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:7][C:2]([Cl:1])=[N:3][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1ccc(-c2nn3c(N4CCOCC4)cc(Cl)nc3c2Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 50.1 %

Procedure:
There was dissolved, in methylene chloride (2 mL), 5-chloro-2-(4-methyl-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (44.4 mg, 0.135 mM), then N-bromo-succinimide (27.1 mg, 0.152 mM) was added to the resulting solution and the mixture was stirred at room temperature for 40 minutes. This reaction liquid was diluted with a saturated aqueous ammonium chloride solution and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was then distilled off and the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:10) to thus obtain the title compound (27.6 mg, yield: 50%).