Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[N:28]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:34]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)(=[O:36])=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=S(=O)(Cl)N1CCOCC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)N1CCOCC1

Procedure:
The title compound, white solid (24.6 mg, 60.2%), MS (ISP) m/z=481.2 [(M+H)+], was prepared in accordance with the general method of example 76 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol) and morpholine-4-sulfonyl chloride.
Reaction SMILES: CO[C:3]1[C:11]2[O:12][C:13]([CH:15]=[CH:16][C:10]=2[CH:9]=[C:5]2[CH:6]=[CH:7][O:8][C:4]=12)=[O:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O>O>[CH:6]1[C:5]2=[CH:9][C:10]3[CH:16]=[CH:15][C:13](=[O:14])[O:12][C:11]=3[CH:3]=[C:4]2[O:8][CH:7]=1
Reactant: COc1c2occc2cc2ccc(=O)oc12
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Product: O=c1ccc2cc3ccoc3cc2o1
Reaction time: 0.25 h

Procedure:
One hundred ml of CDV is pipetted into a sterile container. One ml of 8-methoxypsoralen (8-MOP, 10mg/ml in dimethyl sulfoxide) and one ml of ascorbate stock solution (1M ascorbate in sterile deionized H2O) are added to the container. The mixture is incubated 15 minutes in a 37° C. water bath. After incubation the mixture is transferred to another sterile vessel and allowed to equilibrate in an argon atmosphere for 5 minutes. After equilibration the mixture is placed under a long wavelength ultraviolet light source at a temperature of 10° C. for 2 hours. The incident light intensity is approximately 15 mW/cm2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:27][CH2:26]2)=[N:23][CH:24]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Yield: 74.7 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)piperidin-4-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (423 mg, 75%) as a yellow solid: ESI MS m/z 566 [C28H32BrN5O3+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4](O)[CH3:5])[CH3:2].C(Cl)Cl.N1C(C)=CC=CC=1C.[F:18][C:19]([F:32])([F:31])[S:20]([O:23]S(C(F)(F)F)(=O)=O)(=[O:22])=[O:21]>O>[O:23]([CH2:2][CH2:1][O:3][CH2:4][CH3:5])[S:20]([C:19]([F:32])([F:31])[F:18])(=[O:22])=[O:21]
Reactant: CCOC(C)O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: CCOCCOS(=O)(=O)C(F)(F)F
Temperature: -5 °C

Procedure:
25 g of ethoxyethanol was placed in a round bottom flask provided with a stirrer piece therein, which was connected to a nitrogen bubbler to replace the air in the flask by dry nitrogen. 141 ml of methylene chloride was added and 33 ml of 2,6-lutidine was further added, followed by cooling down to −10 to 0° C., dropping 57 ml of trifluoromethanesulfonic acid anhydride in one hour and continuing agitation under the cooling conditions for one hour. 100 ml of distilled water was added to the reaction solution, and an organic phase was separated, washed with 100 ml of distilled water and dried with anhydrous sodium sulfate, followed by removing the sodium sulfate by filtration and distilling off the solvent under reduced pressure. The resulting residue was distilled under a reduced pressure of 150 Pa at 30° C. to obtain 57 g of a 2-ethoxyethyl triflate fraction.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH:39]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH3:40])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(C(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(C(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.87 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(1-phenylethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.24 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.1 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.07 g, 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[Mn]([O-])(=O)(=O)=[O:9].[K+].[OH2:14]>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:14])[NH:4][N:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(C)[nH]n1
Reactant: O
Agent: [K+]
Product: Cc1cc(C(=O)O)[nH]n1

Procedure:
A mixture of 3,5-dimethylpyrazole (5.19 g, 54 mmol) and potassium permanganate (9.0 g, 57 mmol) in water (40 ml) was heated on the steam bath until the purple color had practically disappeared (about 15 min.). The second portion of potassium permanganate (9.0 g, 57 mmol) was added slowly, allowing time for complete decolorization before each addition. A very exothermic reaction accompanied by some foaming occurred. The reaction mixture was filtered while hot and the maganese dioxide was washed with boiling water (4×20 ml). The filtrate was concentrated in vacuo and concentrated hydrochloric acid was added (5 ml), lowering the pH to 3-3.5. The reaction mixture was evaporated to dryness and exhaustive trituration with boiling, absolute ethanol afforded, after recrystallization from absolute ethanol, 5.1 g (75%) of the acid.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:37])[C@H:15]([OH:36])[C@H:16]([C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)C1C=CC=CC=1.[OH:38]O.[Li+].[OH-]>C1COCC1.O>[C:29]([O:28][C:26]([C:25]1[CH:24]=[C:23]([C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C@@H:15]([OH:36])[C:14]([OH:38])=[O:37])[CH:35]=[CH:34][CH:33]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1cccc([C@H](c2ccccn2)[C@@H](O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc([C@H](c2ccccn2)[C@@H](O)C(=O)O)c1
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-hydroxy-3-oxo-1-pyridin-2-ylpropyl}benzoate from the previous step (0.068 g, 0.135 mmol) in THF (2 mL), was added 35% hydrogen peroxide (0.061 mL, 0.541 mmol) dropwise, then 1.0M LiOH (0.271 mL, 0.271 mmol) in H2O (0.4 mL). The reaction was stirred for 1.5 hours, at which time HPLC indicated incomplete reaction so additional 35% hydrogen peroxide (0.030 mL, 0.271 mmol) and 1.0M LiOH (0.135 mL, 0.135 mmol) in H2O (0.2 mL) were added and stirring continued for 1 hour. HPLC analysis showed complete consumption of starting material. The mixture was quenched with 10% aqueous Na2SO3 (1 mL) and saturated aqueous NaHCO3 (1 mL), diluted with H2O (20 mL), and washed with 2×20 mL CH2Cl2. The aqueous layer was acidified with 10% aqueous citric acid, extracted with 2×30 mL CH2Cl2, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give (2R,3R)-3-[3-(tert-butoxycarbonyl)phenyl]-2-hydroxy-3-pyridin-2-ylpropanoic acid as a yellow oil (0.020 g, 43%). TPLC RT=1.44 min, method B; M+H=344.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([Br:10])[C:3]=1[CH3:11].CS(C)=O.CC(C)([O-])C.[K+].[Cl:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1Cl>C1(C)C=CC=CC=1>[Br:10][C:4]1[C:3]([CH3:11])=[C:2]([CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][C:28]1[CH:27]=[CH:26][C:25]([N+:30]([O-:32])=[O:31])=[CH:24][C:23]=1[Cl:22])[NH2:1]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(N)c(C)c(Br)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(N)c(C)c(Br)c1Oc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
Into a dry 250 milliliter round bottom flask equipped with a magnetic stirrer and nitrogen inlet was added 4-amino-2-bromo-3,6-dimethylphenol (11.94 grams, 55.3 mmol) prepared in Part B and dry dimethylsulfoxide (118 milliliters). Potassium t-butoxide (7.26 grams, 64.65 mmol) was added portionwise under nitrogen and the mixture was stirred at room temperature for 0.5 hours. Solid 3,4-dichloronitrobenzene (13.33 grams, 70.52 mmol) was then added and the reaction mixture was heated at 50° C. for 48 hours. After cooling the mixture was diluted with toluene and washed successively with saturated NH4Cl solution (3x) and with 5% NaOH solution until the aqueous washes remained colorless. This was followed by washes with water and brine, drying over Na2SO4 and solvent removal under reduced pressure to afford the crude product (9.4 grams) as a dark red-brown oil. Flash column chromatography on 650 grams of silica gel (3:1 hexane:ethyl acetate) afforded pure 3-bromo-4-(2 -chloro-4-nitrophenoxy)-2,5-dimethylaniline (4.7 grams, 12.6 mmol, 23%) as a yellow-brown solid. H'-NMR (CDCl3) 8.42 (d, J=2 Hz, 1H), 8.01 (d,d; J=2, 9 Hz; 1H), 6.55 (d, J=9 Hz, 1H), 6.58 (S, 1H), 3.73 (brS, 2H), 2.28 (S, 3H), 2.06 (S, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:31]=[C:32]1[NH:45][C:35]2=[N:36][CH:37]=[C:38](/[CH:40]=[CH:41]/[C:42](O)=[O:43])[CH:39]=[C:34]2[O:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][N:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1)[C:42](=[O:43])/[CH:41]=[CH:40]/[C:38]1[CH:39]=[C:34]2[O:33][C:32](=[O:31])[NH:45][C:35]2=[N:36][CH:37]=1
Reactant: CNCc1cn(C)c2ccccc12
Reactant: O=C(O)/C=C/c1cnc2[nH]c(=O)oc2c1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2[nH]c(=O)oc2c1
Yield: 23 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(1-methyl-1H-indol-3-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(2-oxo-2,3-dihydro-oxazolo[4,5-b]pyridine-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.075 g, 23%) was prepared as a light brown solid: 1H NMR (300 MHz, CDCl3) δ 8.28-8.24 (m, 1H), 7.82 (d, J=15.4 Hz, 1H), 7.71-7.49 (m, 2H), 7.37-6.87 (m, 5H), 4.88-4.86 (m, 2H), 3.78 (s, 3H), 3.16-3.12 (m, 3H); MS (ESI) m/e 363 (M+H)+.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][Si:10]([O:13][CH3:14])(Cl)Cl.[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH:9]([SiH2:10][O:13][CH3:14])[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[Si](C)(Cl)Cl
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CO[SiH2]C(C1CCCCC1)C1CCCCC1
Yield: 80 %

Procedure:
The THF solution of cyclohexyl magnesium chloride as prepared above was added dropwise to the methylmethoxydichlorosilane solution obtained in Example 7, in the same manner as in Example 3(c), to effect the Grignard reaction. The post-treatment of the resulting Grignard reaction solution was carried out in the same manner as in Example 3(c), except that the saturated aqueous ammonium chloride solution used in Example 3(c), was used in a reduced amount of 80 ml instead of 120 ml. The organic layer was separated and was fractionally distilled under a reduced pressure, thereby to afford 39 g of dicyclohexylmethylmethoxysilane as a fraction boiling at 128° C.-129° C./7 mm Hg (yield; 80%).
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH2:13]([NH2:15])[CH3:14].CO.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:15][CH2:13][CH3:14]
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNCc1cccc([N+](=O)[O-])c1C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
A mixture of 2-methyl-3-nitrobenzylchloride (0.50 g, 2.7 mmol) and ethylamine (2.76 g, 61.2 mmol) in THF (10 ml)/MeOH (5 ml) was stirred at ambiend temperature for 48 h. The solvent was reduced and the recidue was dissolved in EtOAc/aq. K2CO3 solution. The aqueous phase was extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give the title compound 0.46 g (86%) as a yellow oil.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16]([NH2:18])=[O:17]>CN(C)C=O>[CH2:6]([O:5][C:3]([CH:2]1[CH2:15][C:16](=[O:17])[NH:18][C:1]1=[O:9])=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
To a solution of diethyl malonate (6.1 ml) in N,N-dimethylformamide (30 ml) are added 60% sodium hydride (1.6 g) at 0° C. and, after 8 minutes, chloroacetamide (1.87 g). After stirring at room temperature for 3.5 hours, the mixture in neutralized with acetic acid and extracted with ethyl acetate. The extract is washed with water and concentrated to give 2,5-dioxopyrrolidine-3-carboxylic acid ethyl ester. Oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.[N:25]1([C:31](=[O:33])[CH3:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CCOC(C)=O>[C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:14][N:13]=3)=[O:10])=[CH:4][CH:3]=2)[CH2:27][CH2:26]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(Cc1ccc(Cl)nc1)Nc1ccc(-c2cccc(F)c2)cn1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(CC(=O)Nc3ccc(-c4cccc(F)c4)cn3)cn2)CC1

Procedure:
2-(6-Chloropyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 140-1 (100 mg, 0.29 mmol) was heated with 1-(piperazin-1-yl)ethanone (0.8 ml) at 108° C. for 4 hours. The mixture was dissolved in EtOAc (30 ml), washed with water (40 mL), and dried over Na2SO4. After concentration by evaporation, the residue was subjected to reverse phase HPLC to afford 2-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 140 as solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]=1[NH:15][C:16]1[CH:17]=[C:18]([C:22]([NH:24][CH2:25][C:26]([NH:28][CH:29]([C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=2)[CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[O:23])[CH:19]=[CH:20][CH:21]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]=1[NH:15][C:16]1[CH:17]=[C:18]([C:22]([NH:24][CH2:25][C:26]([NH:28][CH:29]([C:36]2[CH:37]=[C:38]([Cl:43])[CH:39]=[C:40]([Cl:42])[CH:41]=2)[CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCCCC2)c1)c1cc(Cl)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCCCC2)c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To the product from Example 188 (370 mg, 0.00057 mole) in H2O (20 mL) and CH3CN (15 mL) was added LiOH (192 mg, 0.0046 mole). The reaction mixture was stirred at room temperature for 3 hours. The pH was lowered to ~2.5 with TFA and the product was isolated by RPHPLC to yield the title compound (280 mg after lyophilization) as a white solid.
Reaction SMILES: COC[O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[P:16]([C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:22]=1[O:32]COC)[C:17]([CH3:20])([CH3:19])[CH3:18].C(Cl)(=O)C>C(OCC)(=O)C.CO>[OH:32][C:22]1[C:23]([C:28]([CH3:30])([CH3:31])[CH3:29])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=1[P:16]([C:6]1[CH:7]=[C:8]([CH3:15])[CH:9]=[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]=1[OH:4])[C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: COCOc1c(P(c2cc(C)cc(C(C)(C)C)c2OCOC)C(C)(C)C)cc(C)cc1C(C)(C)C
Solvent: CC(=O)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(P(c2cc(C)cc(C(C)(C)C)c2O)C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To an ethyl acetate/methanol=1/1 solution (60 mL) of bis(2-methoxymethoxy-3-tert-butyl-5-methylphenyl)(tert-butyl)phosphine (1.01 g, 2 mmol) was added acetyl chloride (0.79 g, 10.0 mmol) at room temperature, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure to quantitatively obtain bis(2-hydroxy-3-tert-butyl-5-methylphenyl)(tert-butyl)phosphine as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[C:42]([C:41]1[CH:44]=[C:37]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:18])([F:19])[F:20])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:38]=[N:39][CH:40]=1)#[N:43]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(SC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(SC(F)(F)F)c(F)c3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(3-fluoro-4-((trifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 205.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.10 min, m/z=504.3 [M+H]+, m/z=502.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.83 (dd, J=8.72, 4.33 Hz, 1H) 2.84 (d, J=11.29 Hz, 1H) 3.13-3.25 (m, 2H) 3.34-3.41 (m, 1H) 4.14-4.24 (m, 1H) 4.87 (d, J=3.51 Hz, 1H) 7.65 (dd, J=8.91, 1.88 Hz, 1H) 7.74 (t, J=8.16 Hz, 1H) 7.95 (dd, J=11.80, 2.13 Hz, 1H) 8.07 (d, J=2.38 Hz, 1H) 8.38 (t, J=2.07 Hz, 1H) 8.78 (d, J=2.26 Hz, 1H) 8.88 (d, J=2.13 Hz, 1H) 9.01 (d, J=2.01 Hz, 1H) 10.43 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:28])([F:27])[CH:24](O)O.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:22][C:23]([F:28])([F:27])[CH2:24][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reactant: OC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NCC(F)(F)F)c3)c12
Reaction time: 16 h

Procedure:
To a mixture of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate and 2,2,2-trifluoroethane-1,1-diol in CH2Cl2 (242 μL) at 0° C. was added sodium cyanoborohydride (32.0 mg, 0.509 mmol). The reaction mixture was allowed to stir for 16 hours and then neutralized with 2M aqueous sodium carbonate and extracted with ethyl acetate (×3). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions containing the desired product were concentrated until only the water layer remained. The water layer was neutralized with saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-{3-[(2,2,2-trifluoroethyl)amino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C17H16F3N4O2 [M+H]+: 365, found 365. 1H NMR (600 MHz, DMSO-D6) δ 12.92 (s, 1H), 8.87 (s, 1H), 8.25 (s, 1H), 7.21 (t, 1H, J=7.63 Hz), 7.00 (s, 1H), 6.86 (m, 2H), 6.37 (m, 1H), 3.94 (m, 2H), 3.83 (q, 2H, J=7.04 Hz), 0.81 (t, 3H, J=7.04 Hz).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:3][C:4]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=2[CH:6]=[O:7])=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: COc1ccc(C=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
Sodium hydride (0.66 g) was added in portions to a stirred solution of 3.90 g of 2-hydroxy-4-methoxybenzaldehyde in N,N'-dimethylformamide (70 mL) under nitrogen. To the resulting milky, green mixture was added 1,4-dichloro-2-nitrobenzene (4.47 g). The reaction was placed in an oil bath and stirred at 90° C. for 16 hours. The reaction Was then evaporated and the residue partitioned between chloroform (75 mL) and 1N NaOH (50 mL). The layers were separated and the aqueous layer Was extracted with chloroform (75 mL). The chloroform extracts were combined and washed With Water (75 mL) and brine (75 mL), dried over magnesium sulfate, and evaporated in vacuo. The orange solid was recrystallized from ethyl acetate/iso-propyl ether to yield 3.86 g (53.9%) of product as light yellow, shiny crystals.