Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCOC.[C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH2:22][CH:23]([CH2:26][CH3:27])[CH:24]=O)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Zn].O>[CH2:26]([CH:23]1[CH:24]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21][CH2:22]1)[CH3:27]
Reactant: CCC(C=O)CSc1ccccc1C(=O)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Solvent: O
Product: CCC1C=C(c2ccccc2)c2ccccc2SC1
Yield: 77.3 %

Procedure:
To a mixture of 2.61 g (0.04 mole) of zinc dust and 60 mL of DME was added 7.5 g (0.048 mole) of TiCl3. The reaction mixture was held at reflux for 2 h. A solutiom of 2.98 g (0.01 mole) of 11 was added dropwise in 1 h. The reaction mixture was held at reflux for 18 h, cooled and poured into water. The organic was extracted into ether. The ether layer was washed with brine and filtered through Celite. The filtrate was dried over MgSO4 and concentrated. The residual oil (2.5 g) was purified by HPLC to give 2.06 g (77%) of 12 as an oil in the second fraction.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[C:16]1([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Reactant: Sc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(NN=C(Sc2ccccc2)C(C)=O)cc1
Yield: 84.7 %

Procedure:
The reaction of 392 mg of 1-chloro-1-[(4-methoxyphenyl) hydrazono]-2-propanone, 220 mg of thiophenol and 280 ul of triethylamine in 6 ml of ethanol as in Example 11 yielded 440 mg of 1-[(phenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 120°-123° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: OB(O)c1ccccc1F
Product: Nc1c(F)cc(-c2ccccc2F)cc1F
Yield: 91.8 %

Procedure:
The title compound (0.492 g) was prepared from 4-bromo-2,6-difluoroaniline (0.5 g, 2.4 mmol) and 2-fluorophenylboronic acid (0.436 g, 3.12 mmol) as a yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.51 (td, J 1.5, 7.9, 1H), 7.38-7.31 (m, 1H), 7.29-721 (m, 2H), 7.14 (d, J 8.6, 2H), 5.44 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:19]=[CH2:20]>>[F:24][C:23]([F:26])([F:25])[C:22]([NH:21][CH2:18]/[CH:19]=[CH:20]/[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]([OH:17])([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[CH:3]=1)=[O:27]
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: CCCC(O)(C#Cc1cccc(Br)c1)CCC
Product: CCCC(O)(C#Cc1cccc(/C=C/CNC(=O)C(F)(F)F)c1)CCC

Procedure:
4-((3-bromophenyl)ethynyl)heptan-4-ol was coupled with N-allyl-2,2,2-trifluoroacetamide following the procedure described in Example 123 to give (E)-2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)allyl)acetamide as a pale yellow oil. Yield (0.082 g, 10%): 1H NMR (400 MHz, DMSO-d6) δ 9.68 (t, J=5.4 Hz, 1H), 7.42-7.39 (m, 2H), 7.30 (t, J=8.0 Hz, 1H), 7.23 (dt, J=7.6, 1.4 Hz, 1H), 6.51 (d, J=16.0 Hz, 1H), 6.29 (dt, J=16.0, 6.0 Hz, 1H), 5.13 (s, 1H), 3.95 (t, J=5.4 Hz, 2H), 1.60-1.40 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][OH:13])[CH3:9]>C1(C)C=CC=CC=1>[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][O:13][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH3:9]
Reactant: CN(C)CCCO
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCN(C)C
Temperature: 25 °C
Reaction time: 70 h
Yield: 100.1 %

Procedure:
Diketene (2.54 mL, 33.0 mmol, 1.30 equiv) was added to a solution of 3-(N,N-dimethyl)aminopropan-1-ol (3.00 mL, 25.4 mmol, 1.00 equiv, Aldrich) in toluene (30 mL) and the mixture was stirred at room temperature for 70 hours. The solvent was removed to afford 4.76 g of brown oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=O.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N+:3]([CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6])#[C-:1]
Reactant: COC(=O)C(Cc1ccccc1)NC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C(Cc1ccccc1)C(=O)OC
Temperature: 0 °C

Procedure:
Methyl 2-(formylamino)-3-phenylpropanoate 2i (2.00 g, 9.7 mmole) was dissolved in 20 ml of dichloromethane and cooled to 0° C. After addition of triethylamine (4.88 g, 48.3 mmole), phosphorous oxychloride (2.22 g, 14.5 mmole) dissolved in 10 ml of dichloromethane was then slowly added dropwise. The initially colorless solution turned yellow, with the formation finally of an orange solid. After stirring for 1 hour in an ice bath potassium carbonate solution (0.8 M in water, 39 ml) was slowly added dropwise. To work up the mixture the phases were separated. The organic phase was first of all washed twice with water, each time 20 ml, and then once with 20 ml of saturated NaCl solution. The solution was dried over sodium sulfate and concentrated by evaporation. The product was used without further purification for the next stage.
Reaction SMILES: [C:1]([N:4]1[CH2:21][CH2:20][C:7]2([NH:11][C:10](=[O:12])[C@H:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.C[Si]([Cl:27])(C)C>CC(CC)=O>[ClH:27].[C:1]([N:4]1[CH2:5][CH2:6][C:7]2([NH:11][C:10](=[O:12])[C@H:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH2:20][CH2:21]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
8-Acetyl-3-(S)-benzyl-1,4,8-triazaspiro[4,5]decan-2-one (300 mg, 1.0 mmol) was dissolved in ethyl methyl ketone (2 ml), treated with water (21 μL) and TMSCl (290 μL) and stirred overnight. The solid precipitated in this process was filtered off, washed with ether and dried in vacuo. The product 8-acetyl-3-(S)-benzyl-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 330 mg (96%).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:5]=2[O:4]1.ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:21][CH2:20][C:3]1([CH2:2][F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:30])[C:6]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:5]=2[O:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FCC1(CF)C=C(c2ccccn2)c2cc(I)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: [O-][n+]1ccccc1C1=CC(CF)(CF)Oc2ccc(I)cc21
Yield: 23.1 %

Procedure:
To a mixture of 1.04 g of 2,2-bisfluoromethyl-6-iodo-4-(2-pyridyl)-2H-1-benzopyran and 20 ml of methylene chloride was added 0.78 g of m-chloroperbenzoic acid (70%) with stirring under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and then stirred at room temperature for 25 hours. Potassium carbonate solution was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.25 g of oily 2-(2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-yl)pyridine N-oxide represented by the following formula.
Reaction SMILES: [H-].[Na+].[CH:3]([C@H:16]1[N:21]2[CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:20]2[CH2:19][N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:33]I.O>CN(C)C=O>[CH:3]([C@H:16]1[N:21]2[CH2:22][C@@H:23]([O:25][CH3:33])[CH2:24][C@H:20]2[CH2:19][N:18]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H](O)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](C(c3ccccc3)c3ccccc3)N2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium hydride (60% in mineral oil, 14.9 mg) was added into a solution of tert-butyl (4R,7S,8aS)-4-benzhydryl-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (126.8 mg) in N,N-dimethylformamide (1.5 ml) under ice-cooling. After being stirred for 0.5 hour at the same temperature, methyl iodide was added to the reaction mixture. And this mixture was stirred for 12 hours at room temperature. Then the reaction mixture was poured into water (10 ml). The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (1:2) as an eluent to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-methoxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (100.5 mg).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=[CH:17][C:18](=O)[CH3:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>CO>[C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=[CH:17][C:18](=[N:22][OH:23])[CH3:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: CC(=O)C=CC1CCCN1C(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C=CC1CCCN1C(=O)OCc1ccccc1)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred solution of the compound from step 24e above (5.29 g, 19.3 mmol) in 30 mL of methanol were added, in small portions, 1.34 g (19.36 mmol) of hydroxylamine HCl and 1.59 g (19.36 mmol) of sodium acetate. The reaction mixture was stirred at room temperature for 1 hr, then the solvent was removed. The residue was suspended in 30 mL of water and extracted with ether. The extract was dried over Na2SO4 and concentrated to afford the title product as a syrup (5.34 g, 96% yield). IR 3328, 3030, 2880, 1685, 1444, 1415, 1303, 1181, 1115, 1021, 937 cm-1.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:14])=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[F:14][C:8]1[CH:9]=[C:10]([OH:13])[CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: O=C(CCCl)Nc1ccc(O)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(O)cc(F)c2N1
Temperature: 160 °C

Procedure:
3-Chloro-N-(2-fluoro-4-hydroxyphenyl)propanamide (2.1 g) was mixed with anhydrous AlCl3 (7 g) and heated at 160° C. overnight. The resultant mixture was treated with 1N HCl and extracted with EtOAc. After isolation of the organic layer and removal of solvents under reduced pressure, the desired crude product (1.8 g) was collected as light brown solids.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)#[N:17]>C1C(O)=CC=CC=1C>[CH3:9][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:3]([NH:2][C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[NH:17])[CH:8]=1
Reactant: Cc1ccc(-c2ccccc2)c(N)c1
Reactant: N#CN1CCOCC1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1ccc(-c2ccccc2)c(NC(=N)N2CCOCC2)c1

Procedure:
A mixture of 2-amino-4-methylbiphenyl hydrochloride (7.7 g) and 4-cyanomorpholine (5.9 g) in m-cresol (45 ml) was heated at 90°-95° C. for 15 hours to yield N-(4-methyl-2-biphenylyl)morpholine-4-carboxamidine (m.p. 154°-155° C.) which was recrystallised from hexane.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].C(OCC)(=O)C>C(O)C>[CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.7 %

Procedure:
1-Indanone (2.5 g, 19 mmol) was dissolved in ethanol (25 ml), and the solution was mixed with sodium borohydride (790 mg, 21 mmol) and stirred at room temperature for 3 hours. The reaction solution was mixed with ethyl acetate, washed with hydrochloric acid (1 N) and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 2.4 g (18 mmol, 93%) of the title compound.
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11](=[O:19])[CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:8][C:7]([C@@H:20]2[CH2:23][C@H:22]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:21]2)=[N:6]1)(C)(C)C>C(O)(C(F)(F)F)=O>[N:14]1([CH2:13][CH2:12][C:11]([NH:10][C:9]2[NH:5][N:6]=[C:7]([C@@H:20]3[CH2:21][C@H:22]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:23]3)[CH:8]=2)=[O:19])[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: CC(C)(C)n1nc([C@H]2C[C@@H](OC(=O)NCC3CCCCC3)C2)cc1NC(=O)CCn1cccn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCn1cccn1)Nc1cc([C@H]2C[C@@H](OC(=O)NCC3CCCCC3)C2)n[nH]1

Procedure:
A solution of cyclohexylmethyl-carbamic acid cis-3-[1-tert-butyl-5-(3-pyrazol-1-yl-propionylamino)-1H-pyrazol-3-yl]-cyclobutyl ester from Step A (122 mg) in TFA (2 mL) was heated at 120° C. in a microwave apparatus for 10 min. The solution was concentrated and the residue was dissolved in EtOAc. The resulting solution was washed sequentially with portions of saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford the title product as a white solid. MS (M+H)+=415.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:15][C:16]([OH:18])=[O:17])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
4-methoxy-3-nitro-benzaldehyde (compound of Example 5; 1.05 g, 5.79 mmol) and malonic acid (1.32 g, 1.27 mmol) were dissolved in pyridine (20 mL) under stirring and piperidine (1 mL) was added to the pyridine solution. The reaction mixture was heated at 75° C. to 80° C. for 3 h, after which the temperature was further increased to 120° C. and maintained at this temperature for 6 h. At the end of the reaction, pyridine was evaporated, followed by addition of aqueous HCl (1:1) to obtain pH ˜4. The solid obtained was filtered, washed with cold water and dried.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:8]([C:24]#[N:25])[CH:7]=[N:6][N:5]2[CH:26]=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>C(Cl)Cl.CCOC(C)=O>[C:24]([C:8]1[CH:7]=[N:6][N:5]2[CH:26]=[C:2]([O:1][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])[C:3]([CH3:27])=[C:4]2[C:9]=1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)#[N:25]
Reactant: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
To a solution of 397A (32 mg, 0.090 mmol) in CH2Cl2 (1 ml) was added Tf2O (18 μl, 0.099 mmol) at −10° C. The reaction mixture was stirred for 5 min, diluted with EtOAc, washed with brine, dried and concentrated to give 397 (42 mg, 95%) LCMS Found: (M+H)+=489.0
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH:12]2[C:16]([F:18])([F:17])[C:15]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].CO>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH:12]2[C:16]([F:18])([F:17])[CH:15]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:14][CH2:13]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CN=C(c3cccnc3F)C2(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC2CNC(c3cccnc3F)C2(F)F)cc1
Reaction time: 3 h

Procedure:
To a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-3-yl 4-methylbenzenesulfonate (18.0 g) in tetrahydrofuran (180 mL) was added sodium borohydride (3.68 g) under ice-cooling, methanol (90 mL) was further added, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate. To a suspension of sodium hydride (9.74 g) in tetrahydrofuran (100 mL) was added dropwise a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate in tetrahydrofuran (100 mL) under ice-cooling, 15-crown-5 (32.2 g) was added, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→3:1) to give the title compound as a colorless solid (yield 6.35 g, 72%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[CH3:18][CH:19]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>O1CCCC1>[C:9]([C:7]1[CH:8]=[C:3]([CH2:2][NH:32][C:29]2[CH:28]=[CH:27][C:26]([NH:25][CH:19]([CH3:18])[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:31][CH:30]=2)[CH:4]=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)CCC(C)Nc1ccc(N)cc1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Product: CC(C)CCC(C)Nc1ccc(NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
4Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran. In a separate conical flask N(1,4-Dimethyl-pentyl)-benzene-1,4-diamine (3.28 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottom flask containing solution of 4-Bromomethyl-2,6-di-tert-butyl-phenol was kept in oil-bath at temperature 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. N(1,4-Dimethyl-pentyl)-benzene-1,4diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature. Product was separated by solvent evaporation. The product was purified using silica gel column chromatography. Product was identified by 1H-NMR. The yield of 2,6-di-tert-butyl-4-{[4-(1,4-dimethyl-pentylamino)-phenylamino)methyl}-phenol is 2. 29 g (67%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:15]=[CH:16][C:17]=1B1OC(C)(C)C(C)(C)O1>>[F:11][C:12]1[CH:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][C:34]2[N:35]=[CH:36][CH:37]=[CH:38][N:39]=2)[CH:15]=[CH:16][C:17]=1[C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3Oc3ncccn3)cc2F)OC1(C)C
Reactant: Brc1ccc2[nH]cnc2c1
Product: Fc1cc(-c2ccccc2Oc2ncccn2)ccc1-c1ccc2[nH]cnc2c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 5-bromo-1H-benzo[d]imidazole and 2-((3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-yl)oxy)pyrimidine. MS (ESI): mass calcd. for C23H15FN4O, 382.12; m/z found, 383.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 9.31 (s, 1H), 8.52-8.45 (d, J=4.9, 2H), 7.95 (s, 1H), 7.92-7.87 (d, J=8.6, 1H), 7.79-7.70 (d, J=8.6, 1H), 7.59-7.55 (dd, J=7.7, 1.7, 1H), 7.55-7.47 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.32 (dd, J=12.0, 1.7, 1H), 7.30-7.23 (dd, J=8.1, 1.2, 1H), 7.13-7.08 (t, J=4.8, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[CH3:27][C@H:28]1[O:33][C@@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>ClCCl>[Cl:17][C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[C:8]([C:6]2[O:7][C:3]([CH2:2][N:30]3[CH2:29][C@H:28]([CH3:27])[O:33][C@H:32]([CH3:34])[CH2:31]3)=[CH:4][N:5]=2)[CH:16]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CBr)o3)cc(Cl)cc21
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
4-[5-(Bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole (0.580 g, 1.28 mmol) was dissolved in dichloromethane (5 ml) and (2R,6S)-2,6-dimethylmorpholine (0.317 ml, 2.56 mmol) added. The reaction mixture was stirred at RT for 3 h then the solvent removed under a stream of nitrogen. The resultant yellow solid was dissolved in dichloromethane (5 ml) and washed with water (2×2.5 ml). The layers were separated (hydrophobic frit) and the organic evaporated in vacuo to give the title compound as a pale yellow solid (0.60 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 103.1 %

Procedure:
To a solution of 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.71 mmol) (as prepared in the previous step) in DCM (3 mL) was added N-bromosuccinimide (NBS) (0.13 g, 0.71 mmol), and the reaction stirred at RT for 10 h. The reaction was diluted with EtOAc (10 mL) and washed with NaHCO3 (2×10 mL) and brine (10 mL). Concentration of the organic layer gave 0.26 g (100%) of the title compound as a yellow foam. Mass spectrum (ESI, m/z): Calcd. for C16H23BrN2O2, 355.1 (M+H), found 355.1.