Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C@:5]12[C@@:12]3([CH3:30])[CH2:13][C@H:14]([OH:29])[C@@:15]4([F:28])[C@H:24]([C@@H:11]3[CH2:10][C@H:9]1[CH2:8][NH:7][CH2:6]2)[CH2:23][C@H:22]([F:25])[C:21]1[C@:16]4([CH3:27])[CH:17]=[CH:18][C:19](=[O:26])[CH:20]=1)(=[O:4])[CH3:3].[CH3:31][C:32]1[O:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O)=O>C(#N)C>[C:2]([C@:5]12[C@@:12]3([CH3:30])[CH2:13][C@H:14]([OH:29])[C@@:15]4([F:28])[C@H:24]([C@@H:11]3[CH2:10][C@H:9]1[CH2:8][N:7]([CH2:36][C:35]1[O:38][C:32]([CH3:31])=[CH:33][CH:34]=1)[CH2:6]2)[CH2:23][C@H:22]([F:25])[C:21]1[C@:16]4([CH3:27])[CH:17]=[CH:18][C:19](=[O:26])[CH:20]=1)(=[O:4])[CH3:3]
Reactant: Cc1ccc(C=O)o1
Reactant: CC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: Cl
Solvent: CC#N
Solvent: O=CO
Product: CC(=O)[C@@]12CN(Cc3ccc(C)o3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 140 °C
Yield: 68.2 %

Procedure:
In a closed vessel, a mixture of compound 177 (306 mg, 0.692 mmol), 5-methylfurfural (344 μl, 3.46 mmol), TEA (97 μl, 0.692 mmol) and formic acid (266 μl, 6.92 mmol) in acetonitrile (15 ml) is heated under microwave irradiation for 15 minutes at 140° C. LC-MS shows that the reaction is complete. The solution is partitioned between AcOEt and a saturated solution of NaHCO3, the aqueous phase is extracted with AcOEt and the combined organic layers are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give a oil which is purified by silica gel chromatography (eluent AcOEt/petroleum ether 1/1). Trituration with petroleum ether affords the title compound (236 mg, 0.472 mmol, 68.2% yield).
Reaction SMILES: [F:1][C:2]([F:7])([CH2:5][NH2:6])[CH2:3][NH2:4].C(N(CC)CC)C.[Cl:15][C:16]1[N:25]=[C:24](Cl)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:27])[CH:22]=2)[N:17]=1.O>ClCCl>[Cl:15][C:16]1[N:25]=[C:24]([NH:4][CH2:3][C:2]([F:7])([F:1])[CH2:5][NH2:6])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:27])[CH:22]=2)[N:17]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCC(F)(F)CN
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2nc(Cl)nc(NCC(F)(F)CN)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
To a solution of 2,2-difluoropropane-1,3-diamine (1.1 g, 10 mmol) and triethylamine (1.4 mL, 10 mol) in dichloromethane (15 mL) was added a solution of 2,4-dichloro-6-methylquinazoline (500 mg, 2.36 mmol) in dichloromethane (5 mL) dropwise. After being stirred at room temperature overnight, the resulting mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10-25% methanol in dichloromethane) to afford 41.8 mg of the desired product as a white solid (yield was 62%). MS obsd. (ESI+) [(M+H)+] 287.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH:15]=[O:16])[CH2:7][CH2:6]2.[OH-:17].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CCC(C=O)=C2
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)CCC(C(=O)O)=C2
Yield: 76.8 %

Procedure:
A mixture of 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbaldehyde (2.2 g, 10 mmol) in EtOH (30 mL) was treated with a solution of silver nitrate (5.0 g, 30 mmol) in water (16 mL). A solution of NaOH (6.0 g, 150 mmol) in water (50 mL) was then added with continuous stirring and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then extracted with DCM and combined organic phase was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column using petroleum ether/ethyl acetate (from 6:1 to 3:1, v:v) as the eluent to give 6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxylic acid (1.8 g, 77%). LC-MS (ES-API); rt 8.23 min; m/z calculated for C13H14O4 [M+H]+ 235.1, found 235.0.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl.O>CO.O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 67.2 %

Procedure:
To a solution of 74 gm potassium hydroxide in 673 mL methanol were added 10.0 gm (74 mMol) 5-fluoroindole and 23.3 gm (151 mMol) 4-piperidone.HCl.H2O. The reaction mixture was stirred at reflux for 18 hours. The reaction mixture was diluted with 1.3 L of water and the resulting precipitate recovered by filtration and dried under reduced pressure to give 10.75 gm (67.2%) of 5-fluoro-3-[1,2,5,6-tetrahydro-4-pyridyl]-1H-indole as a yellow solid.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH:17]=[C:18]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][NH:23][CH2:24]2>COC(O)C>[NH:17]=[C:18]([N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][N:23]([C:2]1[NH:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=1)[CH2:24]2
Reactant: N=C(c1cccc2c1CCNC2)N1CCOCC1
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Agent: COC(C)O
Product: COc1cc2nc(N3CCc4c(cccc4C(=N)N4CCOCC4)C3)[nH]c(=O)c2cc1OC
Temperature: 95 °C
Reaction time: 18 h
Yield: 17.9 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b(0.159 g, 0.62 mmol) and 5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline 28a (0.179 g, 0.69 mmol) in methoxyethanol (10 mL) was heated to 95° C. with stirring for 18 h. the volatiles were evaporated and the residue was purified by flash column eluting with 2% methanol in dichloromethane containing 0.2% of ammonium hydroxide to yield 50 mg of 2-[5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinolin-2-yl]-6,7-dimethoxy-3H-quinazolin-4-one 901. The product was converted to the hydrochloric acid salt, mp. 249-251° C., [M+H]+=450.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]1C[O:13][CH2:12][CH2:11]1.BrC(F)(F)C(OCC)=O.C(=O)CC.C1COCC1.C(=O)CC.C(OC(C)C)(C)C>[Zn].O.C1COCC1>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[CH:12]([OH:13])[CH2:11][CH3:10])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C1CCOC1
Agent: [Zn]
Solvent: CCC=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(F)(F)C(O)CC
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A 500 mL reactor was charged with 24.2 g (370 mmol/1.5 equivalents) of an activated metal zinc and 300 mL of THF (dehydrated), and thereto an ethyl bromodifluoroacetate/THF solution [51.47 g (253.6 mmol/1.0 equivalent) of ethyl bromodifluoroacetate and 80 mL of THF (dehydrated)] was added dropwise. After the dropping, stirring was conducted at room temperature for 20 minutes. Then, a propionaldehyde/THF solution [14.80 g (254.8 mmol/1.0 equivalent) of propionaldehyde and 80 mL of THF (dehydrated)] was added, followed by stirring at room temperature for 30 minutes. Then, water and diisopropyl ether were added to conduct a two-layer separation. The obtained organic layer was washed with diluted hydrochloric acid and water, followed by removing water by magnesium sulfate, conducting a filtration, and distilling diisopropyl ether out, thereby obtaining 41.2 g of the target 2,2-difluoro-3-hydroxypentanoic acid ethyl ester. Upon this, yield was 89%.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.C(O)(C)C.[OH-].[Na+]>O>[C:26]1([C:24]2[N:23]=[C:22]([NH2:32])[N:21]=[C:20]([NH:14][C:13]3[CH:15]=[CH:16][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[N:8]=4)=[CH:11][CH:12]=3)[CH:25]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Reactant: Nc1ccc(Oc2ccnc(C(F)(F)F)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)n3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}aniline (1.0 g, 3.9 mmol) and 4-chloro-6-phenylpyrimidin-2-amine (806 mg, 3.9 mmol) were suspended in water (39 mL) and isopropanol (13 mL) and the mixture was heated at 95° C. for 17 h. After cooling to rt, the mixture was neutralized with 1 N aqueous sodium hydroxide and stirred for 20 min. The precipitate were collected by filtration to afford 6-phenyl-N4-(4-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (1.2 g, 72%) as a yellow solid. 1H NMR (DMSO-d6) δ 9.35 (s, 1H), 8.85 (d, 1H), 7.85-7.91 (m, 4H), 7.42-7.47 (m, 3H), 7.30 (d, 1H), 7.18 (d, 2H), 6.48 (s, 1H), 6.38 (brs, 2H); MS ES 425 (M+H)+, calcd 425, RT=2.53 min.
Reaction SMILES: C([O:3][C:4](=[O:20])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([F:7])[F:6])C.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=[CH:13][C:8]([C:5]([F:6])([F:7])[C:4]([OH:20])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(F)(F)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)C(F)(F)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to the above-described scheme, 2-(biphenyl-4-yl)-2,2-difluoroacetic acid ethyl ester (Compound 2g; 82.9 mg, 0.3 mmol), 1N K2CO3 solution (0.9 mL) and DMF (0.9 mL) were put into an eggplant flask, and the mixture was stirred at room temperature for 18 hours. After the reaction, the reaction mixture was neutralized with 5% HCl solution, extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(biphenyl-4-yl)-2,2-difluoroacetic acid (Compound 4g) was obtained with a yield of 88%.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17][S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:2][C:1]1[S:35][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of N-{2-[(2-acetylhydrazino)carbonyl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.65 g), Lawesson's reagent (0.76 g) and tetrahydrofuran (30 mL) was stirred at 50° C. overnight. The resulting crystals were filtrated, washed with tetrahydrofuran, and dried to give the title compound (0.45 g, yield 71%) as colorless crystals. melting point 308-309° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[CH:5]2.Cl.[NH2:17][C@@H:18]([CH3:22])[C:19]([NH2:21])=[O:20].C(N(CC)CC)C.CO>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:17]([C@@H:18]([CH3:22])[C:19]([NH2:21])=[O:20])[CH:6]=[CH:5]2
Reactant: C[C@H](N)C(N)=O
Reactant: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chloro-5-nitro-1H-isochromen-1-one (230 mg, 0.00102 mol), (S)-2-aminopropanamide hydrochloride (127 mg, 0.00102 mol), triethylamine (142 μL, 0.00102 mol) and methanol (20 mL, 0.5 mol) was stirred at 60° C. for 3 hours. The solvent was removed and the residue purified by flash chromatography to obtain the product as a yellow solid. MS m/z=262.3 (M+H).
Reaction SMILES: C1C2C(=CC=CC=2)C=C1.CCC(C[O:16][C:17](C(N(CC[NH+](C)C)C)=O)([C:24]1[CH:29]=CC=CC=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC.[Cl-].[Br:40]Br>O>[Br:40][C@@H:24]1[CH2:29][C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:17]1[OH:16]
Reactant: BrBr
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: C1=Cc2ccccc2C1
Agent: [Cl-]
Solvent: O
Product: O[C@@H]1c2ccccc2C[C@H]1Br

Procedure:
43.5 g of indene (92 wt %; 0.345 mol), 0.7 g of Triton X-100 and 100 ml of water were put into a 500-ml 3-mouthed flask, and mixed by stirring. Mixing was continued at 60° C. as 27.5 g of bromine (0.172 mol, 0.5 mol/mol of indene) was added dropwise over approximately 3 hours. After this, stirring at 60° C. was continued. The reaction mixture was extracted with ethyl acetate directly after dropwise addition of bromine, and after mixing for a further 1 hour. Yields of trans-2-bromoindan-1-ol were calculated from the hydrogen bromide concentrations in the aqueous phase (by gravimetric titration using silver nitrate), and the quantity of indene in the extraction layer was found by GC by means of a calibration line and used to calculate percent conversion.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:30]=[CH:29][C:18]3[CH2:19][CH2:20][N:21]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:22][CH2:23][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:24]1([N:21]2[CH2:22][CH2:23][C:17]3[CH:16]=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:30]=[CH:29][C:18]=3[CH2:19][CH2:20]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2c(cc1OC1CCNCC1)CCN(C1CCCC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-piperidine-1-carboxylic acid-tert-butyl ester (E5a) (593 mg, 1.43 mmol) was dissolved in dichloromethane (5 ml) and treated with trifluoroacetic acid (3 ml). The solution was stirred at room temperature for 1 hour, concentrated in vacuo and applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title product (E5). MS (ES+) m/e 315 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[C:20](=[O:21])[CH2:19][NH:18][C:17]1=[O:22].C([O-])([O-])=O.[K+].[K+].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1>CN(C=O)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:18]2[CH2:19][C:20](=[O:21])[N:16]([CH2:15][C:5]3[N:4]([CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:8]4[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=4[CH:6]=3)[C:17]2=[O:22])=[CH:34][CH:33]=1
Reactant: CC(C)(C)Cn1c(CN2C(=O)CNC2=O)cc2cnc(C#N)nc21
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)CN(Cc3ccc(Cl)cc3)C2=O)cc2cnc(C#N)nc21
Reaction time: 18 h
Yield: 73.8 %

Procedure:
To a solution of 200 mg (0.61 mmoles) of 7-(2,2-dimethyl-propyl)-6-(2,5-dioxo-imidazolidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 10 ml of DMF, 136 mg (0.98 mmoles) of K2CO3, 138 mg (0.86 mmoles) of p-chlorobenzylchloride in 2 ml of DMF and 142 mg (0.86 mmoles) of KI are added successively at ambient temperature. After being stirred for 18 hours, the reaction mixture is quenched with ice water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: CH2C2:AcOEt=8:1) give 203 mg of desired 6-[3-(4-chloro-benzyl)-2,5-dioxo-imidazolidin-1-ylmethyl]-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 73% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:19]3=[CH:23][CH:24]=[N:25][N:18]3[CH:17]=[CH:16][C:15]=2[C:14]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:11])=[O:10].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[CH2:48]([N:50]([CH2:67][CH3:68])[CH2:51]/[CH:52]=[CH:53]\[Sn](CCCC)(CCCC)CCCC)[CH3:49]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:48]([N:50]([CH2:67][CH3:68])[CH2:51]/[CH:52]=[CH:53]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:19]3=[CH:23][CH:24]=[N:25][N:18]3[CH:17]=[CH:16][C:15]=2[C:14]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:11])=[O:10])[CH3:49]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1ccn1nccc21
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ccn3nccc23)c1C(=O)OC
Yield: 27.3 %

Procedure:
A mixture of methyl 8-(2-bromo-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 2, 0.103 g), tris-(dibenzylideneacetone)-dipalladium (0) (0.025 g), tri-tert-butylphosphonium tetrafluoroborate (0.0127 g) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.265 g) in dioxane (3 mL) was irradiated in the microwave at 80° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20% to give methyl 8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (0.030 g).
Reaction SMILES: [CH3:1][Al](C)C.[C:5]([C:8]1[N:9]=[C:10]([Cl:17])[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:7])[CH3:6]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:17][C:10]1[S:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:5]([OH:7])([CH3:1])[CH3:6])[N:9]=1
Reactant: C[Al](C)C
Reactant: COC(=O)c1sc(Cl)nc1C(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1sc(Cl)nc1C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
A solution of 5.6 ml (11.2 mmol) 2N AlMe3 in toluene was added to a dry ice-acetone bath of 1.14 g (5.2 mol) of methyl 4-acetyl-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 212) in 20 ml dry CH2Cl2. The mixture was allowed to warm to room temperature slowly before being quenched with MeOH. After stirring at room temperature overnight, the mixture was diluted with 1N HCl and stirred 15 min before being diluted with water and extracted twice with EtOAc. The EtOAc was washed with brine, dried (MgSO4) and concentrated to give an oil that was purified by chromatography (50% hexanes in CH2Cl2 with gradient elution to 100% CH2Cl2) affording 720 mg of product as an oil. NMR (CDCl3): 1.5 (s, 6H), 3.8 (s, 3H), 5.7 (s, broad, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>CCOCC>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:24]([NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[S:25])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccccc1
Reactant: Cc1ccccc1COc1cccnc1N
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccccc1COc1cccnc1NC(=S)Nc1ccccc1

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (1.67 g, 0.0078 mol), phenyl isothiocyanate (1.26 g, 0.0093 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 1.8 g (66%), m.p. 150°-151 ° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14](O)=[O:15])[CH2:6][CH2:5]2.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[Cl:51])=[CH:42][C:41]([CH3:52])=[CH:40][C:39]=2[CH3:53]>ClCCl>[Cl:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[C:44]1[C:43]2[C:38](=[C:39]([CH3:53])[CH:40]=[C:41]([CH3:52])[CH:42]=2)[N:37]=[CH:36][C:35]=1[NH:34][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(C)c2ncc(NC(=O)C3(C)CCc4c(C)c(O)c(C)c(C)c4O3)c(-c3ccccc3Cl)c2c1
Temperature: 0 °C
Yield: 18 %

Procedure:
To a solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (1.34 g) in dichloromethane (100 ml) was dropwise added DCC (945 mg) under stirring at a temperature of 0° C. The mixture was stirred at 0° C. for 15 minutes, and 3-amino-4-(2-chlorophenyl)-6,8- dimethylquinoline (1.04 g) was added thereto. Thus resulting mixture was further stirred at 0° C. for an hour and at room temperature for one night. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by a silica gel column chromatography with hexane-ethyl acetate (8:2,V/V), and then crystallized from acetone to give 4-(2-chlorophenyl)-3-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylcarbonyl)amino-6,8-dimethylquinoline (341 mg, 18.0%) as colorless prisms.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27].CNCCNC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[F:26][C:23]1[CH:22]=[C:21]([F:27])[CH:20]=[CH:25][C:24]=1[N:14]1[CH2:15][CH2:16][N:11]2[N:10]=[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:18]=[C:12]2[C:13]1=[O:17]
Reactant: O=C1NCCn2nc(COc3ccccc3)cc21
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1c2cc(COc3ccccc3)nn2CCN1c1ccc(F)cc1F
Temperature: 120 °C
Reaction time: 16 h
Yield: 443.5 %

Procedure:
Copper (I) iodide (6.6 mg, 0.033 mmol) was added to a suspension of 2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (40 mg, 0.16 mmol), 1-bromo-2,4-difluorobenzene (63 mg, 0.033 mmol), N,N′-dimethylethylenediamine (0.01 mL, 0.09 mmol) and K2CO3 (45 mg, 0.033 mmol) in toluene (2 mL). The reaction mixture was stirred at 120° C. for 16 hours. The mixture was filtered through a pad of diatomaceous earth which was washed with AcOEt. The filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(2,4-difluoro-phenyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (52 mg, 92% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 4.02-4.15 (m, 2H), 4.50-4.62 (m, 2H), 5.13 (s, 2H), 6.91-6.99 (m, 3H), 7.01 (d, J=8.4 Hz, 2H), 7.04 (s, 1H), 7.27-7.32 (m, 2H), 7.35 (td, J=8.7, 6.1 Hz, 1H).