Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:41][CH3:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)=[O:12])=[C:6]([C:22]2[CH:27]=[C:26]([C:28](=[O:40])[NH:29][C@@H:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32][CH2:31]3)[CH:25]=[CH:24][N:23]=2)[CH:5]=1)[CH3:2].[CH3:43][NH:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])[C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:44]([CH3:43])[CH2:45][CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:18])[CH:14]=2)=[C:6]([C:22]2[CH:27]=[C:26]([C:28](=[O:40])[NH:29][C@@H:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32][CH2:31]3)[CH:25]=[CH:24][N:23]=2)[CH:5]=1)[CH3:42]
Reactant: CNCCN1CCOCC1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)O)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a mixture of (S)-3-((4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoic acid (1.81 mmol, 1.15 g), N-methyl-2-morpholinoethanamine (2.17 mmol, 0.313 g) and DIEA (12.67 mmol, 1.64 g) in DMF (5 mL) was added HATU (2.17 mmol, 0.826 g), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried and concentrated. The residue was purified by column to give a yellow solid (0.98 g, 79%). MS (ESI, m/z) 689.28 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][CH2:18][C:19](N(OC)C)=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27].Br[C:29]1[S:30][CH:31]=[C:32]([Cl:34])[N:33]=1>C1COCC1>[Cl:34][C:32]1[N:33]=[C:29]([C:19](=[O:20])[CH2:18][CH2:17][N:9]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:6]3[C:7]([N:2]([CH3:1])[C:3](=[O:27])[N:4]([CH3:26])[C:5]3=[O:25])=[CH:8]2)[S:30][CH:31]=1
Reactant: CON(C)C(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Reactant: Clc1csc(Br)n1
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Isopropylmagnesium chloride lithium chloride complex solution (1.3M, 2.93 mL, 3.81 mmol) was added dropwise to a solution of 3-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-N-methoxy-N-methylpropanamide (470 mg, 1.269 mmol) and 2-bromo-4-chlorothiazole (Intermediate Q) (252 mg, 1.269 mmol) in THF (20 mL). The mixture was stirred at room temperature for 45 mins. The reaction was quenched with saturated NH4Cl(aq) and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-70% EtOAc/hexane afforded the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:28]([OH:33])([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:6][CH:5]=1.[CH3:34]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:25])([F:27])[F:26])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:28]([CH2:31][CH3:32])([O:33][CH3:34])[CH2:29][CH3:30])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CCC(O)(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
Sodium hydride (60% in oil, 25.4 mg, 0.635 mmol) was added to a stirred solution of 3-{9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}pentan-3-ol (250 mg, 0.529 mmol) in N,N-dimethylformamide (5.0 mL) at room temperature. After stirring 5 min, methyl iodide (113 mg, 0.794 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (175 mg, 0.360 mmol, 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[N:12]=[C:11]([CH2:20]O)[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C1COCC1.C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[N:12]=[C:11]([CH2:20][Cl:25])[C:10]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CO)nc2ccc(F)cc2c1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(CCl)nc2ccc(F)cc2c1OCc1ccccc1
Reaction time: 1 h

Procedure:
[4-(Benzyloxy)-6-fluoro-3-methylquinolin-2-yl]methanol (4.02 g) was dissolved in THF (50 mL) and toluene (50 mL), and 10 drops of pyridine were added thereto. Thionyl chloride (1.50 mL) was gradually added dropwise thereto under ice-cooling, and the reaction mixture was stirred at the same temperature for 1 hour, and further stirred at room temperature for 1 hour. After the precipitated solid was collected by filtration, ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution were gradually added with stirring to the filtrate under ice-cooling. After the foaming became stable, the organic layer was separated, washed sequentially with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 4-(benzyloxy)-2-(chloromethyl)-6-fluoro-3-methylquinoline (3.85 g).
Reaction SMILES: [NH:1]([C:8]1[C:9](=[O:20])[C:10](=[N:13][C:14]2[CH:19]=[CH:18]C=CC=2)[C:11]=1[OH:12])[C:2]1[CH:7]=[CH:6]C=CC=1.C[C@H]1CN[CH2:25][C@@H:24]([CH3:28])[N:23]1[CH2:29][CH2:30][CH3:31]>>[OH-:12].[OH:12][C:11]1[C:10](=[N+:13]2[CH2:14][C@H:19]([CH3:18])[N:23]([CH2:29][CH2:30][CH3:31])[C@H:24]([CH3:25])[CH2:28]2)[C:9](=[O:20])[C:8]=1[N:1]1[CH2:2][C@H:7]([CH3:6])[N:1]([CH2:2][CH2:7][CH3:6])[C@H:8]([CH3:9])[CH2:11]1
Reactant: CCCN1[C@H](C)CNC[C@@H]1C
Reactant: O=c1c(Nc2ccccc2)c(O)c1=Nc1ccccc1
Product: CCCN1[C@H](C)CN(c2c(O)c(=[N+]3C[C@@H](C)N(CCC)[C@@H](C)C3)c2=O)C[C@@H]1C
Product: [OH-]

Procedure:
A mixture of 1.5 grams of 2-anilino-3-hydroxy-4-(phenylimino)-2-cyclobuten-1-one and 1.9 grams of cis-2,6-dimethyl-1-propylpiperazine is heated at 216°-218° C. for 15 minutes under an atmosphere of dry nitrogen. The product is then isolated as described in Example 5 to give 1-[2-hydroxy-3-(cis-3,5-dimethyl-4-propyl-1-piperazinyl)-4-oxo-2-cyclobuten-1-ylidene]-cis-3,5-dimethyl-4-propylpiperazinium hydroxide inner salt as a pale pinkish brown microcrystalline solid melting at about 202°-204° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C[Al](C)C.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.BrC1C=[C:25]2C([CH2:21][CH2:22][O:23][CH:24]2C(OC)=O)=CC=1>C(Cl)Cl.CO.O>[CH3:15][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[CH2:21][CH2:22][O:23][CH:24]2[C:25]1[NH:3][CH2:2][CH2:1][N:4]=1
Reactant: COC(=O)C1OCCc2ccc(Br)cc21
Reactant: NCCN
Reactant: Cc1ccccc1
Agent: C[Al](C)C
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc2c1CCOC2C1=NCCN1

Procedure:
To 10 minutes ice-bath cooled and stirred solution of ethylenediamine (0.29 ml), trimethylaluminum (2M heptane sol, 2.2 ml) and toluene (10 ml) was added the mixture of methyl 7-bromoisochroman-1-carboxylate (0.5 g) and toluene (10 ml) and the reaction mixture was refluxed for 6 hrs. Water (2 ml), methanol (5 ml) and DCM (5 ml) were added, mixture refluxed for 15 min and participate was filtered off. Organics were evaporated and the title compound (0.38 g) was isolated with the separation method D (2-methoxy-2-methylpropane/MeOH).
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[CH2:9]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH:4]([CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1)[C:23]#[N:24])=[O:5]
Reactant: N#CCc1ccc(Cc2ccccc2)cc1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(C=O)c1ccc(Cc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
To a suspention of sodium methoxide (64.26 g) in toluene (2.5 l) was added dropwise at 0° C. a mixture of ethyl formate (88.14 g) and 4-benzylphenylacetonitrile (189.69 g) with stirring. After 30 minutes, ice bath was removed. After 20 hours, ice water (2.6 l) was added to the reaction mixture, and the aqueous layer was separated. The organic layer was washed with 0.5N sodium hydroxide aqueous solution (500 ml×5). The aqueous layer and the washings were combined, adjusted to acid with conc. hydrochloric acid, and stirred at 0° C. for 30 minutes. The precipitate was separated by filtration, washed, and dried to give the title compound.(152.22 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C(O[CH2:19][CH3:20])(OCC)(OCC)C.[C:21](O)(=O)[CH3:22]>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:4](=[N:5][C:21]1[CH:22]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:19][CH3:20])[CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1ccccc1N
Reactant: CCOC(C)(OCC)OCC
Product: CCc1ccccc1N=C(C)Nc1ccccc1CC
Temperature: 195 °C
Yield: 53.7 %

Procedure:
Following the procedure for Taylor and Ehrhart ((Taylor, E. C. et al., J. Org. Chem. 28:1108 (1963)), a stirred solution, under N2, of 2-ethylaniline (2.14 g, 17.7 mmol), triethyl orthoacetate (1.37 g, 8.5 mmol) and glacial acetic acid (0.45 ml, 7.9 mmol) was refluxed at 95°-110° for 2.5 hours. The resulting clear light brown solution was heated (oil bath temperature was 195° C.) under vacuum (30 mm Hg) and the volatile materials were recovered through a short distillation head. The brown oil residue was dissolved in 10 ml of diethyl ether then extracted with 10 ml of 0.6N sodium carbonate. The layers were separated and the aqueous layer was extracted with 2×10 ml of diethyl ether. The combined organic layers were dried (Na2SO4) and the solvent removed at reduced pressure to give 1.15 g of light brown solid. Distillation (bulb to bulb, 190°-200°/0.5 ram) gave 1.13 g of light brown oil that solidified on standing. Crystallization from 20 ml of boiling petroleum ether gave 595 mg of white crystals, Mp 80°-82° C. Recrystallization of 421 mg from 2 ml of boiling petroleum ether gave 380 mg of white granular crystals Mp 80°-81.5° C.
Reaction SMILES: C(N(CC)CC)C.[C@H:8]12[CH2:14][C@H:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl[C:23]1[N:24]=[N:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1>C1(C)C=CC=CC=1>[C:29]1([C:26]2[N:25]=[N:24][C:23]([N:12]3[CH2:13][C@@H:8]4[CH2:14][C@H:11]3[CH2:10][N:9]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:28][CH:27]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1ccc(-c2ccccc2)nn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(-c2ccccc2)nn1
Temperature: 100 °C
Yield: 49.2 %

Procedure:
Triethylamine (20 mL) was added to a suspension of t-butyl (S,S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.43 g, 17.3 mmol, Aldrich Chemical Company) and 3-chloro-6-phenylpyridazine (3.30 g, 17.3 mmol, Aldrich Chemical Company) in toluene (50 mL) and the mixture was heated under nitrogen at 100° C. for 7 days. The dark mixture was cooled to room temperature, and the resulting precipitate was isolated by filtration, washed with toluene (15 mL) and dried under vacuum to provide the title compound as an off-white solid (3.00 g). The filtrate was concentrated and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate, to provide additional product (0.41 g, total yield 3.41 g, 56%): MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].CCCCC.[C:10]([N:14]=[N:15][C:16]1(Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])([CH3:12])[CH3:11].[Cl-].[Na+]>C(O)(C)C.O>[C:10]([N:14]=[N:15][C:16]1([N:3]=[C:2]=[O:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: N#C[O-]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCCCC
Solvent: O
Product: CC(C)(C)N=NC1(N=C=O)CCCCC1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 48.7 grams (0.6 moles) of potassium cyanate in 250 ml of 75% aqueous isopropanol in a 2 liter jacketed reactor, cooled to 5° C., was added 371 grams (0.5 moles) of a 27.4% pentane solution of 1-t-butylazo-1-chlorocyclohexane holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional 90 minutes at room temperature, 300 ml of water added and the reaction stirred until the sodium chloride dissolved. The product was extracted with 300 ml pentane, the pentane extract washed successively with water, 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 100 grams (94.6% crude yield) of a yellow liquid. The product has a sharp band at approximately 2225 cm-1 which is indicative of the isocyanato band in these compounds.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH3:18][O:19][C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[O:19][CH3:18])[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CO/C=C/c1cccc(B(O)O)c1OC
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C/c1cccc(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)c1OC
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
A mixture of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (200 mg, 0.599 mmol), {2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}boronic acid (D101) (187 mg, 0.899 mmol), tripotassium phosphate (318 mg, 1.499 mmol) and Pd(Ph3P)4 (69.3 mg, 0.060 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (2 mL) was stirred at 120° C. (Microwave) for 10 min. The reaction mixture was poured to water. Then the mixture was extracted with EA. The combined organic layers were washed with water and then dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to give 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-{2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazole (D102) (152 mg). MS (ES): C21H21ClN2O3S requires 416.1. found 417.1 (M+H+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][CH:21]=[O:22]
Reactant: COc1ccccc1CCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccccc1CCC=O
Yield: 85.4 %

Procedure:
Meanwhile, a solution of 760 mg of dimethyl sulfoxide in 2 ml of methylene chloride was added dropwise to a solution of 740 mg of oxalyl chloride in 12 ml of methylene chloride at -60° C., with stirring, and the mixture was stirred at the same temperature for 10 minutes. At the end of this time, a solution of 640 mg of 3-(2-methoxyphenyl)propanol (prepared as described above) in 3 ml of methylene chloride was added dropwise to the mixture, and the mixture was stirred for a further 10 minutes. 1.96 g of triethylamine were then slowly added dropwise to the mixture at the same temperature. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 minutes and then mixed with water. The methylene chloride layer was separated, dried over anhydrous magesium sulfate, and concentrated by evaporation under reduced pressure. The oily residue thus obtained was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 540 mg of 3-(2-methoxyphenyl)propanal as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][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:6]=2[N:7]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[CH:9][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:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a mixture of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (150 mg, 0.307 mmol), 4-fluorophenylboronic acid (64 mg, 0.457 mmol) and Pd(Ph3P)2Cl2 (22 mg, 0.031 mmol) in dioxane (3 mL), aq. Na2CO3 (100 mg, 0.943 mmol) (1.0 mL) was added. The mixture was stirred at 100° C. for 1 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, which was eluted with 5-15% EtOAc in hexane to give 2-chloro-N-cyclopropyl-5-(4-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (121 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[N:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[CH:10][C:3]=23)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
The 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (500 mg, 3.24 mmol) and piperazine-1-carboxylic acid tert-butyl ester (603 mg, 3.24 mmol) were dissolved in 11.0 mL of NMP then treated with diisopropylethyl amine (845 μL, 4.85 mmol). The yellow solution was heated to 80 C overnight to completion and was allowed to cool to room temperature. The solution was diluted with ethyl acetate, poured into diluted NaHCO3 solution, and extracted with ethyl acetate. The combined organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude material as a tan solid. The material was triturated with DCM/hexanes to afford the 4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a cream-colored solid (824 mg, 84%). 1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.06 (s, 1H), 4.05 (m, 4H), 3.67 (m, 4H). LCMS (APCI+) m/z 305 [M+H]+; Rt=2.14 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:34][CH2:35][CH3:36])=[C:16]([CH:23]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.FC(F)(F)C(O)=O>C(Cl)Cl.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17]([C:21]#[N:22])=[C:16]([CH:23]4[CH2:24][NH:25][CH2:26]4)[C:15]=3[O:34][CH2:35][CH3:36])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
A solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate (peak 1 enantiomer from step 5) (2.2 g, 4.2 mmol) in methylene chloride (11 mL) was treated with trifluoroacetic acid (11 mL) dropwise and stirred at room temperature for 30 min. The reaction mixture was concentrated to an oil that was reconcentrated from ethanol (2×) to give a residue. This material was dissolved in a minimum amount of methanol, added dropwise to ice cooled saturated sodium bicarbonate solution (100 ml), and extracted several times with 2:1 dichloromethane/isopropanol to give the desired product (1.8 g, quantitative) that was used without further purification. A small amount of the desired product was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.47 (s, 1H), 6.23 (q, J=7.0 Hz, 1H), 4.37-4.26 (m, 1H), 3.91-3.61 (m, 6H), 2.54 (s, 3H), 1.71 (d, J=7.1 Hz, 3H), 1.32 (t, J=7.0 Hz, 3H). LCMS for C20H23ClN7O (M+H)+: m/z=412.2; Found: 412.1.
Reaction SMILES: [N+:1]([C:4]1C=CC=[CH:11][C:5]=1[O:6]CC(=O)C)([O-:3])=[O:2].[C:15]1(C)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[OH:23]>>[N+:1]([CH:4]([O:23][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:5](=[O:6])[CH3:11])([O-:3])=[O:2]
Reactant: Cc1ccccc1
Reactant: CC(=O)COc1ccccc1[N+](=O)[O-]
Reactant: CO
Product: CC(=O)C(Oc1ccccc1)[N+](=O)[O-]

Procedure:
2624 g of o-nitrophenoxyacetone crystals (˜98%) from the 1st stage, step d), were dissolved at room temperature in a mixture of 11 307 g of methanol and 1290 g of toluene at 40° C., in order to obtain an about 17.6% solution of nitrophenoxyacetone.