Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][C:12]([CH3:15])=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][C:12]([CH3:15])=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8])=[C:16]=[S:17]
Reactant: Cc1ncn(-c2ccc(N)cc2C#N)n1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Cc1ncn(-c2ccc(N=C=S)cc2C#N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
Step G (3): Dichloromethane (100 mL) was added to a flask charged with 5-amino-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (6.59 g, 33.1 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (7.68 g, 33.1 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography (0-5% EtOAc/chloroform) linear gradient to afford 5-isothiocyanato-2-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (5.19 g, 15.88 mmol, 56% yield) as a yellow solid. LC-MS (M+H)+ 242.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C)C=O>[F:20][CH:16]([F:21])[O:14][C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2cc(OC(F)F)cnc12
Temperature: 100 °C
Yield: 15.8 %

Procedure:
A solution of 8-nitro-quinolin-3-ol (CAS25369-37-3) (500 mg, 2.63 mmol) in dimethylformamide (5 ml) was treated with sodium chlorodifluoroacetate (481 mg, 3.15 mmol). The mixture was heated to 100° C. overnight under a nitrogen atmosphere. For the workup, the reaction mixture was cooled to room temperature, then saturated aqueous sodium carbonate solution and dichloromethane were added. The organic layer was separated, dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a gradient of cyclohexane/ethyl acetate=9:1 to 8:1 as the eluent yielding 100 mg (16%) of the 3-difluoromethoxy-8-nitro-quinoline as a yellow solid; (calculated) C10H6F2N2O3 [240.2]; (found) [M+H]+=241.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:19]Br>O>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][C:18]=1[Br:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrBr
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)O)cc1Br

Procedure:
37.5 g (0.15 mole) of p-octyloxy benzoic acid are put in suspension in 108 ml of deionized water. The temperature of the reaction medium is brought to between 50° C. and 55° C. and 8.7 ml (0.17 mole) of bromine are added at this temperature over a period of 7 hours 30 minutes.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O>[C:7]1([CH:6]([OH:13])[CH2:4][CH3:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: O
Product: CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43 %

Procedure:
To a Schlenk flask containing degassed dry dichloromethane (10 mL) was added the polymer of Example 2 (28.6 mg, 0.1 mmol based on the biphenyl subunit) and diethylzinc (0.42 mL, 4 mmol). The resulting mixture was stirred at r.t. for 2.5 h. Benzaldehyde (0.2 mL, 2 mmol) was then added and the reaction mixture was stirred at r.t. for 112 h. Water (5 mL) and 1N HCl (5 mL) were added to quench the reaction. The polymer catalyst was filtered off and recovered. The organic layer in the filtrate was separated and the aqueous layer was extracted with dichloromethane. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. 1H NMR spectroscopic analysis of this crude product indicated a complete conversion and the ratio of 1-phenyl-1-propanol to benzyl alcohol (a side product) was 53:47. Column chromatography on silica gel (eluent: EtOAc/hexanes=1/4) gave 1-phenyl-1-propanol as a colorless liquid (117 mg, 43%). GC analysis on a chiral column (β-Dex capillary column, Supelco Company) showed an ee of 13%.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13].[C:16](Cl)(=[O:18])[CH3:17].N1C=CC=CC=1>>[CH3:1][C:2]1[CH2:6][CH2:5][CH:4]([C:7]([CH3:9])=[CH2:8])[C:3]=1[CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][O:13][C:16](=[O:18])[CH3:17]
Reactant: C=C(C)C1CCC(C)=C1CC(C)(C)CO
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: C=C(C)C1CCC(C)=C1CC(C)(C)COC(C)=O
Yield: 95 %

Procedure:
This compound was prepared by esterifying 32 g (0.25 mole) of the product from Example 3 with 24 g (0.3 mole) of acetyl chloride and 24 g (0.3 mole) of pyridine at from 15° to 20° C. On working up in the conventional manner, the ester was obtained in 95% yield; boiling point: 88°-90° C/25 mm Hg; nD25 : 1.4743; the structure was confirmed by the nuclear resonance spectrum. Fragrance: musk-like, floral; good tenacity.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1.C(N(CC)C(C)C)(C)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl>[C:46]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([S:25]([NH:28][C@H:29]([C:33]([OH:35])=[O:34])[CH:30]([CH3:32])[CH3:31])(=[O:26])=[O:27])=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[O:11])=[CH:7][C:6]=2[CH:36]=1)(=[O:48])[CH3:47]
Reactant: CC(=O)Cl
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4cc(N)ccc4o3)cc2)cc1)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-[(4′-{[(5-amino-1-benzofuran-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine-Wang resin (0.3 g), from Example 7, was suspended in methylene chloride (6 mL). To the suspension was added N,N-diisopropylethylamine (6.0 equiv.) and acetyl chloride (3.0 equiv.). The reaction was allowed to proceed at room temperature for 0. h and the reagent was removed by filtration. The resin was washed with methylene chloride (2×), methanol and methylene chloride (2×) before being treated with a 95% solution of TFA in methylene chloride (5 mL) and agitated at room temperature for 2 h. The solution was collected by filtration and the solvent was removed via vacuum. The crude product was then purified by flash chromatography to give N-{[4′-({[5-(acetylamino)-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valine. LCMS MH+ (m/z) 550. 1H NMR (300 MHz, DMSO-d6): δ 10.50 ppm (s, 1H), 9.92 ppm (s, 1H), 8.00-7.34 ppm (m, 12H), 3.33 ppm (m, 1H), 1.89 ppm (s, 3 H), 1.76 ppm (m, 1H), 0.63 ppm (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].Br[C:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:9]=1>C(O)(=O)C>[CH:4]([O:6][C:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:9]=1)([CH3:5])[CH3:3]
Reactant: CC(C)O
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(Br)n2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(O)ccc3c(OC(C)C)n2)n[nH]1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
NaH (155 mg) was added to a solution of Propan-2-ol (2 ml) and the resulting mixture was stirred for 1 hour. 1-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (100 mg) was added to the mixture, and the mixture was heated at 170° C. for 30 minutes under microwave irradiation. The reaction mixture was acidified to PH=3 with acetic acid and evaporated to oil. The residue was treated with water (50 ml) and the resulting solid was collected to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (50 mg). LC-MS: m/e 299 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[C:19](Br)=[CH:18][S:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:30])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[C:19]([C:31]#[N:32])=[CH:18][S:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CN(Cc1cc(-c2cscc2Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(Cc1cc(-c2cscc2C#N)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 71 %

Procedure:
To a solution (5 mL) of tert-butyl{[5-(4-bromo-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (470 mg) in N,N-dimethylformamide were added zinc cyanide (215 mg) and tetrakis(triphenylphosphine)palladium (212 mg) and the mixture was sufficiently degassed. The mixture was stirred with heating at 120° C. for 18 hr and cooled to room temperature. Water and ethyl acetate were added and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 297 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:42]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[OH:54])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[OH:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[N:42]1[CH2:47][CH2:46][N:45]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:44][CH2:43]1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 58.7 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (466 mg, 1.08 mmol, 59%) was obtained.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10].[CH2:11](I)[CH:12]=[CH2:13]>C1COCC1>[CH2:13]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH:12]=[CH2:11]
Reactant: CCc1ccccc1Br
Reactant: C=CCI
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1ccccc1CC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 8.53 g (350 mmol) of magnesium in 270 mL of dry THF was added 50 g (270 mmol) of 1-bromo-2-ethyl benzene. The temperature was maintained at 50° C. during addition, then was heated under reflux. After 1 h, the solution was cooled to -78° C. under N2, and 54.42 g (324 mmol) of allyl iodide was added dropwise. The mixture was allowed to warm to room temperature, stirred for an additional 2 h, then cooled to 0° C. The reaction was quenched by addition of 2M HCl and 500 mL of ether and the layers were separated. The organic layer was washed with 30 mL of saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The oily residue was filtered through silica gel with 20% ethyl acetate-hexane and the eluate was concentrated to afford the crude 1-allyl-2-ethylbenzene as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:24])[NH:17]2>CN(C)C=O>[Br:11][C:12]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:1][O:2][CH3:3])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:24])[NH:17]2
Reactant: COCCl
Reactant: Cc1cc(O)c2[nH]c(=O)ccc2c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1cc(C)c(Br)c2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methoxymethyl chloride (410 μL) was added to a suspension of potassium carbonate (1.24 g) in a solution of 5-bromo-8-hydroxy-6-methyl-1H-quinolin-2-one (480 mg) in dimethylformamide (9 mL) at 0° C. The reaction mixture is stirred for 18 hours at room temperature, filtered, the solvent removed in vacuo, and the product purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1)[C:28](=[O:29])[C:27]1[CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: Clc1ccccc1-c1ccncc1NCc1ncco1
Product: CS(=O)(=O)c1cc(C(=O)N(Cc2ncco2)c2cnccc2-c2ccccc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-chloro-phenyl)-pyridin-3-yl]-oxazol-2-ylmethyl-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 21 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless solid (157 mg, 42%). MS (ESI): m/z=536.065 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[C:3]=1[F:10].CC([O-])(C)C.[K+].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[Cl:9][C:4]1[C:3]([F:10])=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:17])[CH:23]=1)[NH2:1]
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)c(Cl)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of 4-amino-2-chloro-3-fluorophenol (11 g, 68.3 mmol) and potassium 2-methylpropan-2-olate (8.4 g, 75.2 mmol) in DMA (120 mL) was stirred at RT under N2 for 0.5 h, treated with 2,4-dichloropyridine (9.1 g, 62.1 mmol), and heated at 80° C. for 8 h. The mixture was concentrated to dryness, the residue treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography to afford 3-chloro-4-(2-chloropyridin-4-yloxy)-2-fluoroaniline (10 g, 59%). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d, J=5.6 Hz, 1H), 6.98-6.96 (m, 2 H), 6.88 (dd, J=5.6 Hz, 2.0 Hz, 1 H), 6.80 (t, J=9.2 Hz, 1 H), 5.57 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[CH:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15]>O1CCCC1>[Br:8][C:4]1[N:3]=[C:2]([CH:14]([OH:15])[N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCN(C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(O)c2cccc(Br)n2)CC1
Reaction time: 1 h

Procedure:
2,6-Dibromopyridine (5.45 g, 23.01 mmol) was dissolved in tetrahydrofuran (27.3 mL) and cooled to −78° C. under argon after which n-butyllithium (10.40 mL, 26.0 mmol) was added and the solution was stirred for thirty minutes. A solution of tert-butyl 4-formylpiperazine-1-carboxylate (5.00 g, 23.47 mmol) in tetrahydrofuran (8 mL) was added and the solution was stirred at −78° C. for one hour and then for one hour at ambient temperature. The reaction was quenched with saturated sodium bicarbonate (10 mL) and stirred for ten minutes. The product was extracted with ether, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=1)=O.O.[NH2:21][NH2:22]>CN(C1C=CN=CC=1)C>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[NH:22][N:21]=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=1
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)cc1C
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1C
Yield: 90.5 %

Procedure:
Prepared as in Example 104 from (2,3-difluorophenyl)-(4-methoxy-3-methyl-phenyl)-methanone (0.9 g, 3.45 mmol), hydrazine hydrate (1.06 mL, 34 mmol) and DMAP (0.42 g, 3.45 mmol) to give the product (0.80 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:37]1CC[C@H](NC2N=C3C(NC(=O)N3C3C=CC=CC=3OC)=C(C(OCC)=O)N=2)C1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([NH2:37])=[O:21]
Reactant: CCOC(=O)c1nc(N[C@H]2CCNC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CCNC3)nc21
Reaction time: 2 h
Yield: 100 %

Procedure:
(S)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxylate. (S)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.369 g, 0.668 mmol) were dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The solution was stirred for two hours and condensed under reduced pressure to afford the crude title compound (0.300 g, 100%). MS (ESI) m/z 399.3 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH2:21][CH2:22][F:23].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:23][CH2:22][CH2:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: FCCCBr
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CCCF)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 39.4 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.0 g of 1-bromo-3-fluoropropane were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.67 g of 2-(3-fluoropropyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (74)).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:33][N:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C6CNC6)c5)cc4c3)n2n1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C6CN(C)C6)c5)cc4c3)n2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To 3-(1-azetidin-3-yl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (194 mg, 0.4898 mmol) in dichloromethane (9 mL) was added formaldehyde (37% in water, 1.959 mmol, 147 uL). The solution was stirred at room temperature for 15 minutes and then sodium triacetoxyborohydride (260 mg, 1.22 mmol) was added. After 1 hour the solution was diluted with dichloromethane (6 mL) and washed with sodium bicarbonate (6 mL). The aqueous layer was extracted further with dichloromethane (6 mL). The combined dichloromethane layers were washed with brine (12 mL) and dried over Na2SO4. The filtrate was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH:NH4OH, 95:4.995:0.005-80:19.98:0.02) to return the title compound (69 mg, 35% yield). Analytical data presented in Table 2.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[C:17](=[O:18])[C:16]2=[C:19]([Cl:22])[CH:20]=[CH:21][N:15]2[N:14]=[C:13]1[CH:23]([CH:25]1[CH2:27][CH2:26]1)O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:5]([N:12]1[C:17](=[O:18])[C:16]2=[C:19]([Cl:22])[CH:20]=[CH:21][N:15]2[N:14]=[C:13]1[CH:23]([Cl:3])[CH:25]1[CH2:27][CH2:26]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1c2c(Cl)ccn2nc(C(O)C2CC2)n1Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1c2c(Cl)ccn2nc(C(Cl)C2CC2)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
Thionyl chloride (2 M in CH2Cl2, 1.52 ml, 3.04 mmol) was added to solution of 3-benzyl-5-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (0.5 g, 1.52 mmol) and pyridine (0.49 mL, 6.08 mmol) in CH2Cl2 (10 ml) at 0° C. The reaction mixture was stirred at 0° C. for 45 min and then quenched by pouring on to ice. The solution was treated with 1 N HCl (100 mL) and extracted with CHCl3 (3×100 mL). The combined organic extracts were washed with saturated NaHCO3 (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 4/1 hexane/EtOAc to afford the title compound (0.368 g, 70%) as a solid: 1H NMR (DMF-d7) δ 7.96 (m, 1H), 7.47–7.60 (m, 5H), 6.97 (m, 1H), 5.94 (m, 1H), 5.22 (m, 1H), 4.63 (d, 1H, J=9.99 Hz), 2.09–2.12 (m, 1H), 0.98–1.05 (m, 1H), 0.86–0.97 (m, 1H), 0.68–0.71 (m, 1H), 0.23–0.27 (m, 1H); MS (ESI+) 348 (M++H), HRMS (ESI+) calculated: 348.0670 (M++H). found: 348.0686 (M++H).