Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:4][N:3]=1.C(N(CC)CC)C.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:8]([N:7]([C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[C:28](=[O:29])[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCCCCCNc1nnc(C)s1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCN(C(=O)Cc1ccccc1)c1nnc(C)s1
Reaction time: 24 h

Procedure:
N-(5-Methyl-1,3,4-thiadiazol-2-yl)-hexylamine (5.98 g, 0.03 mole) in toluene (60 ml) was stirred together with triethylamine (4.59 ml) and phenylacetyl chloride (4.64 g, 0.03 mole) and refluxed overnight. Further triethylamine (4.6 ml) and phenylacetyl chloride (4 ml) were added and refluxing was continued for a further 24 hours. The mixture was evaporated to dryness, treated with water and extracted with chloroform. The chloroform extract was washed with 2N sodium hydroxide solution and with water, and was dried (Na2SO4), filtered and evaporated to yield the title product as an oil, b.p. 190° C./0.1 mm (8.03 g). This was recrystallised from ethanol to give the title compound as a solid, m.p. 90° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.O.C(=O)(O)[O-].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C(COC)OC>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 47 %

Procedure:
2-Chloropyridine-4-carbonitrile 19 (2.96 g, 21.35 mmol) was dissolved in 100 ml of dimethoxyethane. The solution was added with 70 ml of water, sodium bicarbonate (3 equiv., 5.38 g), [4-(trifluoromethyl)phenyl]boronic acid (1.2 equiv., 4.87 g) and the mixture was then stirred at rt for 5′. The mixture was degassed and placed under argon. A catalytic amount of tetrakispalladium was added and the mixture heated at 100° C. overnight. The solvents were evaporated off and the resulting residue dissolved with ethyl acetate and then washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude was crystallized from ethyl acetate and petroleum ether to give a beige solid. (2.5 g, 47% yield).
Reaction SMILES: [SiH3]O[SiH3].[C:4]1([C@H:10]([CH3:13])[CH2:11][OH:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([CH:10]([CH3:13])[CH2:11][OH:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[C@H](CO)c1ccccc1
Agent: [SiH3]O[SiH3]
Product: CC(CO)c1ccccc1

Procedure:
Furthermore, the purificative deprotections of the chiral silylethers (1f and 1m) were examined in the presence of the corresponding enantiomerically pure alcohols using the triphasic system of FIGS. 2 and 3. The deprotection reaction of 1f (1.0 equiv) proceeded in the presence of (R)-(+)-1-(2-naphthyl)ethanol (1.0 equiv), and 1-(2-naphthyl)ethanol was obtained in 83% total yield in a ratio with 41/59 in P-/S-phases (entry 5). The enantiomeric excess (ee) values of 1-(2-naphthyl)ethanol obtained were >97% and 90% in P- and S-phases, respectively. The chiral silyl ether 1m (1.0 equiv) also underwent the purificative deprotection in the presence of (S)-(−)-2-phenylpropanol (1.0 equiv), and 2-phenylpropanol was obtained in 76% total yield in a ratio with 39/61 in P-/S-phases. The ee values of 2-phenylpropanol were 89% and 87% in P- and S-phases, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11]C)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:1]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:8][C:9]2=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)Cc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccccc32)CC1
Reaction time: 0.5 h
Yield: 130.2 %

Procedure:
Methyl 2-aminophenylacetate (3.0 g, 18.2 mmol) and 1-tert-butoxycarbonyl-4-piperidone (4.5 g, 22.6 mmol) were set stirring in 50 mL of CH2Cl2 under an atmosphere of nitrogen. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was added followed by 1 mL of acetic acid. After 20 h at rt the mixture was quenched by the slow addition of saturated NaHCO3. After stirring for 30 min, the organics were separated, dried (MgSO4), and evaporated to afford 7.5 g of a purple oil. Purification by column chromatography (silica, 10-50% EtOAc/hexanes) gave 3.9 g (62%) of the title compound. TLC (silica, 25% EtOAc/hexanes): Rf=0.15. 1H NMR (400 MHz, CDCl3): 7.25 (m, 2H), 7.01 (m, 2H), 4.40 (m, 1H), 3.53 (s, 2H), 2.83 (m, 2H), 2.32 (m, 2H), 1.70 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]=12.[CH3:14][NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH:16]1([N:15]([CH3:14])[C:2]2[C:3]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][CH:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1c[nH]c2nccc(Cl)c12
Reactant: CNC1CCCCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccnc2[nH]cc([N+](=O)[O-])c12)C1CCCCC1

Procedure:
To a suspension of 4-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (57 mg) in 2-propanol (180 μl) were added N-methylcyclohexanamine (154 μl) and N,N-diisopropylethylamine (50 μl), and irradiated microwave at 120° C. for 15 minutes. The reaction mixture was purified by flash column chromatography over silica gel with a EtOAc/methanol (100:0-60:40) as eluant. then by preparative silica gel thin-layer chromatography with EtOAc as eluant to give a solid. The solid was washed with diisopropyl ether to give N-cyclohexyl-N-methyl-3-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine (7.9 mg) as a yellow solid.
Reaction SMILES: ICI.[CH2:4]([Zn]CC)C.[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:35])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]([CH3:34])=[CH2:33])[C:13]2=[CH:12][CH:11]=1.[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39]>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:35])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]3([CH3:4])[CH2:34][CH2:33]3)[C:13]2=[CH:12][CH:11]=1.[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39]
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reactant: CC[Zn]CC
Agent: COC(C)[Si](C)(C)C
Solvent: ICI
Solvent: Cc1ccccc1
Product: CC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
A solution of diiodomethane (3.7 g, 0.013 mmol) in toluene (10 mL) was cooled in ice-salt bath. Then diethylzinc (1.1M in toluene, 10 mL, 11 mmol) was added dropwise into the above solution slowly. After the addition, the mixture was stirred for 10 min. To the resulting mixture was added a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in Example 267a (800 mg, 1.4 mmol) in toluene (10 mL). The mixture was then allowed to warm to room temperature and stirred for 3 h, quenched with aqueous NH4Cl. The organic layer was separated, washed with water, dried over Na2SO4, purified by column chromatography to give title compound (800 mg).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:28]2[CH2:27][CH:26]=[C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:31])[F:32])[CH:20]=3)[CH2:30][CH2:29]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C(c1ccccc1)c1ccccc1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 1 h
Yield: 34.2 %

Procedure:
8 g of α,α-diphenylacetyl chloride in 50 ml of methylene chloride were added dropwise to a mixture of 8 g (0.035 mole) of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 50 ml of methylene chloride and 4.96 ml of triethylamine at the temperature of 0/+5° C. Stirring is effected for one hour at room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up into ethyl ether, washing is effected with a 0.2M aqueous solution of hydrochloric acid, with water, with an aqueous solution of sodium carbonate and then with water. Drying is effected over sodium sulphate, the solvent is evaporated off under reduced pressure. 5 g of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7]O)(=[O:4])[CH:2]=[CH2:3].[C:9]1([C:19]([OH:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][CH:6]([O:20][C:19]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:21])[CH3:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: C=CC(=O)OCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CC(=O)OC(C)OC(=O)c1cccc2ccccc12
Yield: 82.3 %

Procedure:
To a solution of 2-hydroxyethyl acrylate (1.01 g, 8.7 mmol) and 1-naphthoic acid (1.00 g, 5.8 mmol) in 10 ml of freshly distilled CH2Cl2 was added EDC (1.60 g, 8.7 mmol) and DMAP (cat. amount) at room temperature. The resultant mixture was stirred at room temperature until TLC indicated the disappearance of starting material. The reaction was quenched with a 5% solution of NH4Cl and the mixture was washed with water. After extraction with EtOAc (3×20 ml), the organic layers were dried over anhydrous MgSO4 and purified with column chromatography on silica gel (1:4, EtOAc:hexanes) to give 1.29 g (82%) of naphthalene-1-carbonyloxy-2-ethyl acrylate as a colorless oil. 1H NMR (250 MHz) δ 8.91 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.1 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.57 (m, 3H), 6.49 (d, J=17.3 Hz, 1H), 6.19 (dd, J=17.3, 10.4 Hz, 1H), 5.71 (d, J=10.4 Hz, 1H), 4.66 (m, 2H), 4.58 (m, 2H). 13C NMR (63 MHz) δ 167.2, 165.9, 133.8, 133.6, 131.5, 131.3, 130.5, 128.6, 128.0, 127.8, 126.6, 126.2, 125.7, 124.5, 62.7, 62.3.
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([N:11]([CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:31]C)[CH2:22]1)[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH3:10].[NH4+].[OH-]>O>[CH2:8]([N:11]([CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[OH:31])[CH2:22]1)[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH3:10]
Reactant: CCCN(CCOc1ccccc1)C1CCc2c(cccc2OC)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCCN(CCOc1ccccc1)C1CCc2c(O)cccc2C1

Procedure:
A mixture of pyridine hydrochloride and the product of Example 1 was heated in an oil bath at 200° C. When the reaction was complete (TLC), it was cooled, diluted with H2O, made basic with NH4OH and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (Silica: 8:2 pet ether/EtOAc). The product was dissolved in ether and converted to a hydrochloride salt by the addition of dry ether- HCl. Anal. Calcd. for C21H27NO2. HCl: C, 69.69; H, 7.80; N, 3.87. Found: C, 69.54; H, 7.90; N, 3.87. NMR of the free base (300 MHz, CDCl3): δ7.3-6.6(m, 8H), 4.0(t, 2H), 3.1-2.5(m, 9H), 2.1(m, 1H), 1.7-1.4(m, 3H), 0.9(t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:17]O.P(Br)(Br)[Br:20].O>C(OCC)C>[Br:20][CH2:17][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1c(C(F)(F)F)nn(-c2ccccc2)c1Cl
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1nn(-c2ccccc2)c(Cl)c1CBr
Temperature: -10 °C
Reaction time: 1 h
Yield: 279 %

Procedure:
A solution of 3.0 g (10.9 mmoles) of (5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 60 ml of diethyl ether was cooled to −10° C. Thereto was added 1.0 g (3.8 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.6 g (yield: 95.8%) of 4-bromomethyl-5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole as white crystals.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[OH:20])[CH:10]=[CH2:11].S(C1C=CC(C)=CC=1)(O[CH2:25][C@@H:26]1[O:28][CH2:27]1)(=O)=O>CN(C=O)C>[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][CH2:25][C@H:26]1[CH2:27][O:28]1)[CH:10]=[CH2:11]
Reactant: C=CCOc1ccc(Cl)cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Cl)cc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To 4.0 g (79 mmole) of 60% sodium hydride/mineral oil dispersion in a one liter flask was added 300 ml of hexane. The mixture was swirled briefly, the solid allowed to settle and the supernatant liquid decanted. DMF (500 ml) was added, followed by a solution of 14.6 g (79 mmole) of 2-allyloxy-5-chlorophenol in 100 ml of DMF. The mixture was stirred at room temperature under nitrogen for 30 minutes, then 18.0 g (79 mmole) of (R)-glycidyl tosylate added. The mixture was heated under a nitrogen atmosphere at 80° C. for 24 hours. The solvent was evaporated in vacuum and replaced with 750 ml of methylene chloride. The solution was washed with 500 ml portions of 2N HCl (aq), saturated aqueous sodium bicarbonate, saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum to give 20 g of a crude gum. This was column chromatographed on silica gel using methylene chloride as eluant to give 9.2 g of the title compound as a colorless oil. 1H (CDCl3) singlet, 6.93 δ(1 H); doublet, 6.90 δ(1 H); doublet, 6.80 δ(1 H);.multiplet, 6.05 δ(1 H); doublet, 5.40 δ(1 H); doublet, 5.25 δ(1 H); doublet, 4.55 δ(2 H); doublet of doublets, 4.25 δ(1 H); doublet of doublets, 3.97 δ(1 H); multiplet, 3.35 δ(1 H); triplet, 2.95 δ(2H); triplet, 2.75 δ(1 H).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][CH:22]([CH3:25])[CH:23]=[CH2:24]>>[CH3:21][CH:22]([CH3:25])[CH2:23][CH2:24][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Reactant: C=CC(C)C
Product: CCOC(=O)C1=Cc2ccc(CCC(C)C)cc2OC1C(F)(F)F

Procedure:
The ester from Example 9a, Step 2 was coupled and using a similar protocol as described in Example 611d, Step 1 using the appropriate substitution of 3-methylbut-1-ene (77%): ESLRMS m/z 343.1 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](F)(=[O:35])=[O:34].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([S:33]([C:28]3[C:27]([CH3:26])=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Cc1ccccc1S(=O)(=O)F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.55 g; 1.66 mmol) in THF (25 mL) was added drop wise a solution of n-BuLi in hexanes (1.32 ml; 2.50 mol/l; 3.31 mmol), at −78° C. The resulting mixture was stirred at −78° C., for 30 min. and then 2-methyl-benzenesulfonyl fluoride (0.63 g; 3.64 mmol) was added. After complete addition the mixture was allowed to come to room temperature, and treated with EtOAc and a 5% aqueous NaHCO3-solution. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 4-benzyl-2-[4-(toluene-2-sulfonyl)-phenyl]-morpholine (0.50 g). The required 2-methyl-benzenesulfonyl fluoride was prepared as follows: To a solution of o-toluenesulfonyl chloride (0.70 mL; 4.85 mmol) in CH3CN (15 mL) was added spray-dried KF (1.13 g; 19.4 mmol). The resulting mixture was stirred at RT for 18 hours, treated with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methyl-benzenesulfonyl fluoride (0.68 g).
Reaction SMILES: C[C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[CH2:20](O)C.[BH4-].[Na+].O>CO>[CH3:20][C:19]1[CH:2]=[CH:3][C:4]2[CH2:10][CH:9]([OH:11])[C:8]3[CH:12]=[C:13]([S:16][CH3:17])[CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:18]=1
Reactant: CCO
Reactant: CSc1ccc2c(c1)C(=O)Cc1cc(C)ccc1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ccc2c(c1)C(O)Cc1ccc(C)cc1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.9 G. of 10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin-10-one are suspended in 65 ml. of ethanol and treated with a solution of 1.25 g. of sodium borohydride in 4.3 ml. of water. The mixture is stirred for 2 hours at room temperature. Then, 20 ml. of methanol are added thereto and the resulting mixture is heated at reflux for 15 minutes. Thereafter, the methanol and ethanol are removed by evaporation in vacuo. The residue is extracted with chloroform, the chloroform extracts are washed with water, dried and evaporated in vacuo. The residue is crystallized from diisopropyl ether, and there is obtained 10,11-dihydro- 3-methyl-8-methylthio-dibenz[b,f]oxepin- 10-ol having a melting point of 67°-69° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[C:31]([NH:32][C:33]2[NH:59][C:36]3=[N:37][C:38]([O:54][CH2:55][CH:56]([F:58])[F:57])=[C:39]([C:41](=[O:53])[NH:42][C@H:43]4[CH2:48][CH2:47][C@H:46]([C:49]([F:52])([F:51])[F:50])[CH2:45][CH2:44]4)[CH:40]=[C:35]3[N:34]=2)=[C:30]([Cl:60])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27].CCN(C(C)C)C(C)C.[F:70][C:71]([CH3:76])([CH3:75])[C:72](O)=[O:73]>CN(C=O)C>[Cl:23][C:24]1[C:31]([NH:32][C:33]2[NH:59][C:36]3=[N:37][C:38]([O:54][CH2:55][CH:56]([F:57])[F:58])=[C:39]([C:41](=[O:53])[NH:42][C@H:43]4[CH2:48][CH2:47][C@H:46]([C:49]([F:52])([F:50])[F:51])[CH2:45][CH2:44]4)[CH:40]=[C:35]3[N:34]=2)=[C:30]([Cl:60])[CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][C:72](=[O:73])[C:71]([CH3:76])([F:70])[CH3:75]
Reactant: NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Reactant: CC(C)(F)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(F)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)nc3[nH]2)c1Cl
Reaction time: 72 h

Procedure:
TBTU (1.0 ml of a 0.11 M solution in DMF) is added to a mixture of 2,4-dichloro-3-[6-(trans-4-trifluoromethyl-cyclohexylcarbamoyl)-5-(2,2-difluoro-ethoxy)-3H-imidazo[4,5-b]pyridin-2-ylamino]benzylamine (1.0 ml of a 0.10 M solution in DMF), DIPEA (52 μl, 0.3 mmol) and 2-fluoro-2-methylpropionic acid (1.0 ml of a 0.13 M solution in DMF) and it is stirred for 3 d and the mixture is purified by prep. HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:24][CH3:25])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: CCI
Reactant: Clc1nc(Nc2ccccc2)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A one liter flask is charged with 25.5 g of 2chloro-6-(phenyl-amino)-purine (104 mmol), 16.7 g of K2CO3 (121 mmoles) and 500 ml of DMF. The mixture is stirred for one hour to solubilize K2CO3, followed by addition of ethyliodid (16.1 ml, 200 mmoles). The flask is stirred at RT for 2 hours under argon. Upon completion, the solvent is removed by evaporation under reduced pressure, and the remaining powder is extracted with 150 ml of ethyl acetate, washed with water (3×30 ml) and with 30 ml of a saturated NaCl soln. The aqueous layers are extracted with ethyl acetate (2×150 ml). The combined organic layers are dried (MgSO4), filtered and concentrated. The crude product is stirred with 100 ml of diethyl ether to give a crude yellow powder, which is filtered and dried at 50° C. under HV. 23.08 g (84 mmol, 81% yield) of 2-chloro-9-ethyl-6-(phenyl-amino)-9H-purine are obtained as a white crystalline powder. Rf=0.65 (CH2Cl2/MeOH (95/5); m.p. 158° C.; ESI-MS: 274 (M+H)+; 1H-NMR (d6-DMSO, 200 MHz, TMS): 1.4 ppm (t, 3H, J1=7 Hz, H1), 4.2 ppm (q, 2H, J1=7 Hz, H2), 7.1 ppm (t, 1H, J2=8 Hz, H7), 7.4 ppm (t, 2H, J2=8 Hz, H6), 7.85 ppm (d, 2H, J2=8 Hz, H5), 8.3 ppm (s, 1H, H3), 10.3 ppm (s, 1H, H4).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:24][CH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[C:28](=[O:44])[N:29]([CH:36]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]1=[O:43])[C:30]2=[O:35].C(N(CC)CC)C>CN(C=O)C>[O:43]=[C:37]1[CH:36]([N:29]2[C:28](=[O:44])[C:27]3[C:31](=[CH:32][CH:33]=[CH:34][C:26]=3[CH2:25][NH:24][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)=[O:10])[C:30]2=[O:35])[CH2:41][CH2:40][C:39](=[O:42])[NH:38]1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(Br)n4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A mixture of 6-bromopicolinic acid (0.40 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (25 mL) was stirred at ambient temperature under nitrogen for 2 hours. 4-Aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 16 hours. The solvent was evaporated under vacuum, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting the product with 97:3 methylene chloride-methanol. This material was further purified by preparative HPLC, eluting with 1:1 acetonitrile-water, providing 0.50 g of the purified product in 53% yield: mp 181-183° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.52-2.65 (m, 2H), 2.84-2.93 (m, 1H), 4.96 (d, J=6.3 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.67-7.72 (m, 1H), 7.80-7.82 (m, 2H), 7.90 (dd, J=7.8 Hz, J=1.0 Hz, 1H), 7.97 (t, J=7.6 Hz, 1H), 8.07 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 9.39 (t, J=6.3 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.5, 48.9, 121.7, 121.9, 127.1, 131.2, 131.6, 133.0, 134.8, 138.9, 140.3, 141.0, 151.0, 163.1, 167.0, 167.6, 169.8, 172.8; Anal. calcd for C20H15BrN4O5.0.5H2O: C, 50.01; H, 3.35; N, 11.66. Found: C, 49.97; H, 3.21; N, 11.56.