Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([C:29]1[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.ClCCCl>[CH3:27][C:22]([CH3:28])([CH2:21][C:19]1[S:20][C:16]([C:11]2[CH:10]=[C:9]([NH:8][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:32]=[CH:31][N:30]=3)[CH:14]=[C:13]([CH3:15])[CH:12]=2)=[CH:17][N:18]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(C)(C)Cc1ncc(-c2cc(C)cc(N(C(=O)OC(C)(C)C)c3nccc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)Cc1ncc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
The product from Step 2 (390 mg, 0.708 mmol) was dissolved in CH2Cl2 (8 mL)/TFA (2 mL) and stirred at room temperature for 90 min. The reaction was subsequently diluted with 1,2-DCE and evaporated to dryness. The residue was redissolved in EtOAc, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-50% ethyl acetate in hexanes) afforded 293 mg (92%) of methyl 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoate as a yellow gum. MS ESI: [M+H]+ m/z 451.0. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.80 (d, J=4.9, 1H), 8.00-7.88 (m, 2H), 7.43 (s, 1H), 7.25 (d, J=4.9, 1H), 7.13 (s, 1H), 3.61 (s, 3H), 3.19 (s, 2H), 2.29 (s, 3H), 1.18 (s, 6H). rhSYK activity=+++
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:28]=[C:27]([CH:34]=O)[CH:26]=2)=[CH:21][CH:20]=1>>[C:30]([N:29]1[C:25]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:26][C:27]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[N:28]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Product: Cc1cccc(N2CCN(CCNCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)c1C
Yield: 77.8 %

Procedure:
Compound 22 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.[C:29](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Yield: 88 %

Procedure:
To a mixture of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (7.0 g, 17.1 mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), trityl chloride (5.2 g, 18.8 mmole) in pyridine (50 mL) was added at room temperature and refluxed for 18 hrs. The excess pyridine was evaporated; reaction mixture was diluted with water (250 mL) and washed with 1N dil. HCl (50 mL) extracted with dichloromethane (2×200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 9.8 g of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+]>CC(=O)CC.O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]=2[F:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(C)cc(-c3cccc(F)c3)c2F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]phenol (100 mg, 0.30 mmol, 1.0 eq) and Na2CO3 (58 mg, 0.60 mmol, 2.0 eq) in 2-butanone (10 mL) was added ethyl bromoacetate (75.1 mg, 0.45 mmol, 1.5 eq). The mixture was stirred at room temperature for 3 h. TLC showed the reaction to be incomplete so Cs2CO3 (50 mg, 0.15 mmol, 0.5 eq) was added and the reaction stirred a further 3 h. TLC showed the reaction was still not finished so ethyl bromoacetate (0.2 mL) was added and the reaction stirred for a further 1 h. The solution was then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as a solid (100 mg, 81%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](Cl)=[O:5].I.[CH3:8][N:9]([C:18]([S:20][CH3:21])=[NH:19])[N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C.ClCCl>[CH3:1][S:2][CH2:3][C:4]([N:19]=[C:18]([N:9]([CH3:8])[N:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:20][CH3:21])=[O:5]
Reactant: CSCC(=O)Cl
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCC(=O)N=C(SC)N(C)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
(Methylthio)acetyl chloride (5.6 g) was added portionwise to a solution of methyl 1-methyl-2-(phenylmethylene)hydrazine carboximidothioate hydroiodide (A) (10.4 g) in triethylamine (7.08 g) and dichloromethane (55 ml) and the mixture stirred at room temperature for 2 h. The mixture was washed with water and evaporated to give an oil which was chromatographed using 1:1 ether-petroleum ether (b.p. 60°-80°) followed by ether to give the title compound (4.6 g) as a cream solid, m.p. 68°-70°.
Reaction SMILES: BrC1CCC(=O)CC1.[Na].[C:10]1([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:23][OH:24]>CN(C)C=O>[C:17]1([S:16][CH:10]2[CH2:11][CH2:12][C:13](=[N:23][OH:24])[CH2:14][CH2:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NO
Reactant: c1ccc(Sc2ccccc2)cc1
Agent: O=C1CCC(Br)CC1
Agent: [Na]
Solvent: CN(C)C=O
Product: ON=C1CCC(Sc2ccccc2)CC1

Procedure:
The title compound is prepared by reacting 4-bromocyclohexanone with the sodium salt of phenyl sulfide in dimethylformamide followed by reacting with hydroxylamine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CCOCC.CC(C)=O>[CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1)=[O:3]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 72 h
Yield: 86 %

Procedure:
A mechanically stirred mixture of 1 kg. (7.35 mole) of 3-hydroxyacetophenone, 1.035 kg. (7.5 mole) anhydrous potassium carbonate and 0.945 kg. (7.5 mole) of benzylchloride in 4.1 of acetone was heated at reflux for 24 hours after which 0.1035 kg. (0.75 mole) portion of potassium carbonate and 0.0945 kg. (0.75 mole) portion of benzylchloride were added and refluxing continued. This addition was repeated after 72 hours of refluxing and refluxing continued for 96 hours. The reaction was cooled, filtered and the filtrate concentrated on a rotovapor. The filtrate was then treated with 0.202 kg. (2.0 mole) triethylamine and stirred overnight. The reaction was diluted with 1 liter ether and filtered. The filtrate was evaporated and the residue distilled to yield 1.429 kg. (86%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=[CH:6][C:7]=1[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21].[OH-].[Na+].Cl>C(#N)C>[OH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([N:8]2[C:7]3[CH:6]=[CH:5][C:4]([C:16]([F:17])([F:18])[F:19])=[CH:3][C:2]=3[NH:1][C:20]2=[O:21])[CH2:10][CH2:11]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1[C@H]1CC[C@H](O)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 3-amino-4-(trans-4-hydroxycyclohexylamino)benzotrifluoride (657 mg) in acetonitrile (7 mL) was added 1,1′-carbonyldiimidazole (1.17 g), and the mixture was stirred at 60° C. under nitrogen atmosphere for 3 hours. After adding 1N-sodium hydroxide solution (5 mL), the mixture was stirred at 60° C. for an hour. The mixture was neutralized with concentrated hydrochloric acid at 0° C. The resulting precipitate was collected by filtration and washed successively with water and diethyl ether to give 1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-one (549.5 mg) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Li+].C[Si]([N-:58][Si](C)(C)C)(C)C>C1COCC1.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.[Pd].[Pd]>[CH3:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:58])=[N:3][CH:4]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(N)nc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
To a solution of 2-chloro-5-(2-methyl-4-nitrophenoxy)pyridine (1.13 g, 4.27 mmol), XPHOS (0.097 g, 0.205 mmol) and Pd2 dba3 (0.078 g, 0.0853 mmol) in THF (32 mL) was added LHMDS (8.53 mL, 8.53 mmol). After heating to 65° C. for 1 hour, the mixture was cooled to room temperature and stirred for 16 hours. The mixture was concentrated onto silica and chromatographed (10% methanol in ethyl acetate) to provide the product (0.336 g, 33%).
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.NCCC[C:24]1[NH:25][CH:26]=[CH:27][N:28]=1>>[N:25]1([CH2:10][CH2:6][CH2:7][NH:8][CH:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[CH2:7]2)[CH:26]=[CH:27][N:28]=[CH:24]1
Reactant: NCCCc1ncc[nH]1
Reactant: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Product: O=[N+]([O-])c1ccc(N2CCC(NCCCn3ccnc3)C2)cc1
Yield: 48.2 %

Procedure:
30 g (0.105 mol) of 1-(4-nitrophenyl)pyrrolid-3-yl methylsulphonate (2) were heated at 90° C. for 18 hours with 120 g of aminopropylimidazole (0.958 mol). This mixture was poured into ice-cold water and the product was extracted with dichloromethane. The yellow powder obtained was chromatographed, eluting with dichloromethane/methanol (98/2), and 15.2 g of derivative (7) were recovered (48.2% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.CC(C)([O-])C.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][O:23][CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: BrCC1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](COCC1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1.48 g (3.77 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-14S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 68, Step A) and bromomethylcyclopropane (0.828 mL, 7.54 mmol) in DMF (20 mL) was added sodium t-butoxide (0.544 g, 5.66 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h and then warmed to rt. Then the reaction was stirred at rt for 14 h. The reaction was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: 20%-40% EtOAc/Hexanes, gradient elution) provided the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1>C(O)C>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:20][CH:19]=1)#[N:28]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Solvent: CCO
Product: CCc1cc(NCc2ccc(-c3ccccc3C#N)cc2)n2nccc2n1

Procedure:
5.5 g (30.3 mmol) of the chloride from Example 1, Step B and 6.3 g (30.3 mmol) of 4-aminomethyl-2'-cyanobiphenyl (prepared according to EP 459 136) were heated in 150 ml dry ethanol for 10 h. After removal of the solvent in vacuo yellow crystals formed. These were purified by suspension in acetone and dissolved in ethyl acetate. The solution was washed with 10% sodium carbonate solution, the organic layer dried over sodium sulfate, and evaporated to dryness to give colorless crystals of the title compound,
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1>[OH-].[Na+]>[C:2](=[O:3])([O:4][CH3:5])[O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[CH3:14]
Reactant: Cc1cc(F)ccc1O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Oc1ccc(F)cc1C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
Methyl chloroformate (6.8 ml, 88 mmol) was added over 30 minutes to a solution of 4-fluoro-2-methylphenol (10 g, 79 mmol) in 6% aqueous sodium hydroxide solution at 0° C. The mixture was stirred for 2 hours, then extracted with ethyl acetate (100 ml). The ethyl acetate extract was washed with water (100 ml) and dried (MgSO4) and the solvent removed by evaporation to give 4-fluoro-2-methylphenyl methyl carbonate (11.4 g, 78%) as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:29][C@@:30]2([CH3:33])[CH2:32][O:31]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:29][C@:30]1([CH2:33][O:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH2:32][O:31]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)CO2)cc1
Reactant: CC(=O)Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1OC[C@@]1(C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
To 2-acetamidophenol (90.5 mg, 0.598 mmol) and cesium carbonate (234 mg, 0.718 mmol) was added [(2R)-2-methyloxiranyl]methyl 4-methylbenzene-sulfonate (145 mg, 0.598 mmol) dissolved in DMF (1 ml). The mixture was stirred at room temperature for four hours and then partitioned between ethyl-acetate and water. After extraction the combined organic phases were dried and concentrated in vacuo. The residue was purified on silica (Heptane/EtOAc 3:1-2:1) to give 63 mg (48%) of the title compound.
Reaction SMILES: C([Li])CCC.[CH:6]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]>C1COCC1>[CH3:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][N:18]1[C:19]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COCCOCCBr
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCN1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Butyllithium (1.6 M in hexane, 5 ml) was added dropwise to a stirring solution of 10H-phenoxazine (1.00 g, 5.46 mmol) in THF at −78° C. and continued the stirring for 1 h. To this mixture added 1-bromo-2(2-methoxyethoxy)ethane (1.5 ml, 11 mmol) dropwise and stirring continued for another 1 h at −78° C. The mixture was allowed to warm to RT and stirred overnight, after which the resultant dark orange solution was quenched with water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The crude mixture was purified by chromatography and Kugelrohr distillation to give the product as a pale yellow oil (1.11 g, 72%). Cyclic voltammetry of MEEP in a 0.1 M tetra-n-butylammonium hexafluorophosphate (TBAPF6) in acetonitrile solution shows a reversible redox couple at 0.26 V vs Fc+/Fc.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N(CC)CC)C.[CH3:37][C@H:38]1[CH2:40][O:39]1>C(O)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([CH2:37][C@@H:38]([OH:39])[CH3:40])[CH2:6]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C[C@H](C)O)C1
Temperature: 90 °C

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.032 mmol, from Example 67, Step 1) and triethylamine (18 μL, 0.13 mmol) in ethanol (0.53 mL) was added (S)-(−)-methyloxirane (6.8 μL, 0.097 mmol). The resulting mixture was heated at 90° C. for 3 h, then purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The enantiomers were separated on a Phenomenex Lux Cellulose C-4 column (5 μM, 21.2×250 mm), eluting with 20% ethanol in hexanes, at flow rate of 18 mL/min, to give two enantiomers. First peak (2.7 mg, 18%) retention time 8.9 min; LCMS calculated for C21H27ClFN6O2 (M+H)+: m/z=449.2; Found: 449.1. 1H NMR (DMSO-d6, 500 MHz) δ 8.11 (1H, s), 7.42 (1H, d, J=8.5 Hz), 7.25 (2H, br s), 6.21 (1H, q, J=7.5 Hz), 4.28 (1H, d, J=4.0 Hz), 3.82 (3H, m), 3.62 (3H, s), 3.55 (1H, m), 3.05 (1H, m), 2.97 (1H, m), 2.55 (3H, s), 2.28 (2H, m), 1.70 (2H, d, J=7.5 Hz), 1.00 (3H, d, J=6.0 Hz) ppm. Second peak retention time 10.0 min.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:18])=[N:9][N:10]([CH:15]([CH3:17])[CH3:16])[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.Cl>CCO.O.[Fe]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:18])=[N:9][N:10]([CH:15]([CH3:16])[CH3:17])[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: CC(C)n1nc(Br)c2ccc([N+](=O)[O-])cc2c1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Temperature: 80 °C
Yield: 99.2 %

Procedure:
7-Nitro-2-Isopropyl-4-bromo-2H-phthalazin-1-one (4.6 g, 0.015 mol) was dissolved in a 5:1 mixture of EtOH and water (150 ml). To this solution was added iron powder (2.14 g, 0.039 mol) and concentrated HCl (1 ml), the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to RT and filtered through a pad of celite, the celite was washed with EtOH (100 ml), and the solution was concentrated under vacuum to give the title compound (4.2 g, 98% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO), 7.56 (1H, d), 7.28 (1H, s), 7.13 (1 H, d), 6.47 (2H, s), 5.24-5.09 (1H, m), 1.23 (6H, d); MS (ESI+)=(M+H)+ 282, 284
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[I:25]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([I:25])=[N:17][NH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ncc23)CC1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(I)c23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A solution of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-1H-indazole (5.00 g, 16.5 mmol) in N,N-dimethylformamide is treated with powdered potassium hydroxide (1.85 g, 33.07 mmol) and iodine (4.61 g, 18.2 mmol), stirred at room temperature for 16 h, diluted with ethyl acetate and quenched with 15% aqueous sodium metabisulfite. The phases are separated and the aqueous phase is extracted with ethyl acetate. The extracts and the organic phase are combined, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a crude solid. This solid is purified by column chromatography (silica gel, 10:90 to 15:85 to 20:80 ethyl acetate/hexanes) to afford the title product as a yellow solid, 2.40 g (35% yield) identified by HNMR and mass spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]>C(O)(=O)C.O=[Pt]=O>[CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccncc1NC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC1CCNCC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.8 %

Procedure:
Tert-butyl 4-methylpyridin-3-ylcarbamate (200 mg, 0.96 mmol) was dissolved in glacial acetic acid (5 mL) and treated with PtO2 (200 mg, 1:1 w/w) under an atmosphere of hydrogen. The reaction mixture was stirred at rt for 15 h. The reaction mixture was then filtered through a pad of Celite. The filtrate was neutralized with solid NaHCO3, and extracted with EtOAc (5×50 mL). The organic layer was dried over Na2SO4, concentrated in vacuo to yield the titled compound (160 mg, 77%), which was used for next step without further purification. 1H NMR (400 MHz, CDCl3): δ 4.38-4.21 (m, 1H), 3.32-2.81 (m, 3H), 2.63-2.49 (m, 2H), 2.41-2.32 (m, 1H), 1.78-1.56 (m, 3H), 1.59 (s, 9H), 1.05 and 0.98 (2d, J=6.8 Hz, 3H). ES-MS: m/z [M+1]=215.