Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:27][C@@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[C:11]([CH:26]=1)[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:13])#[N:6]>O.C(O)(=O)C>[C:2]([N:30]1[CH2:31][CH2:32][C@@H:28]([NH:27][C:10]2[CH:9]=[CH:8][C:7]([C:5]#[N:6])=[CH:26][C:11]=2[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=[O:13])[CH2:29]1)(=[O:1])[NH2:3]
Reactant: N#C[O-]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCNC2)cc1OC
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H]2CCN(C(N)=O)C2)cc1OC
Temperature: 60 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
A solution of potassium cyanate (53 mg) in water (1.5 mL) was added to a solution of (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(3-pyrrolidinylamino)benzamide (100 mg) in acetic acid (1.5 mL). The mixture was stirred for 3 hours at 60° C. and then for 2 hours at 90° C. The reaction mixture was concentrated in vacuo and the residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by thin layer chromatography developed with 5% methanol in chloroform. The obtained product was triturated with diethyl ether to give (R)-2-(1-carbamoylpyrrolidin-3-ylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (22 mg) as a powders.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[F:12][C:13]([F:21])([F:20])[C:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:11][C:3]1[C:2]([NH2:1])=[C:9]([Cl:10])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:17]([C:14]1([C:13]([F:21])([F:20])[F:12])[CH2:16][CH2:15]1)=[O:18]
Reactant: NCc1ccc(Cl)c(N)c1Cl
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Nc1c(Cl)ccc(CNC(=O)C2(C(F)(F)F)CC2)c1Cl

Procedure:
The sub-title compound is prepared from 3-amino-2,4-dichloro-benzylamine (0.310 g, 1.01 mmol), 1-trifluoromethyl-cyclopropane carboxylic acid (0.17 g, 1.1 mmol), TBTU (0.39 g, 1.2 mmol) and TEA (0.71 mL) in DMF in analogy to example 3e.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:17])=[CH:5][C:6](=[O:16])[C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].II.[I:20](O)(=O)=O>C(O)C.O.S([O-])([O-])=O.[Na+].[Na+]>[I:20][C:5]1[C:6](=[O:16])[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:17]
Reactant: CCCCCCCCc1c(C)[nH]c(C)cc1=O
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCc1c(C)[nH]c(C)c(I)c1=O
Reaction time: 0.5 h
Yield: 205.8 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-octylpyridin-4(1H)-one (1.17 g) and iodine (0.63 g) in ethanol (15 ml) at 70° was added dropwise a solution of iodic acid (0.22 g) in water (1 ml). After 30 min the mixture was allowed to cool and a few drops of an aqueous sodium sulphite solution added to remove excess iodine. The precipitate was filtered, washed with ethanol and recrystallised from DMF to give the title compound (0.93 g), m.p. 224°-226°, NMR δH (d6 -DMSO) 2.42 (3H, s), 2.3-2.5 (2H, m), 2.2 (3H, s), 1.1-1.45 (12H, m), 0.85 (3H, t).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[F:27][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12](=[O:26])[N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=1)[C:4]([C@@H:2]([NH:1][C:29]1[C:30]3[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][NH:35][C:31]=3[N:32]=[CH:33][N:34]=1)[CH3:3])=[N:5]2
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: FC(F)(F)c1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: C[C@H](Nc1ncnc2[nH]cc(C(F)(F)F)c12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (76 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.4 mL) at 23° C. was added 4-chloro-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (49 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 50 mg of the title compound (44% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.N1CCCCC1>C(O)C>[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]2=[O:1])=[CH:20]1
Reactant: CCOC(=O)C1=C(Nc2ccccn2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccn2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 2.5 %

Procedure:
To a solution of ethyl 4-oxo-2-(2-pyridinylamino)-4,5-dihydrofuran-3-carboxylate (0.080 g, 0.32 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.047 g, 0.32 mmol) in ethanol (2.0 mL), piperidine (0.038 mL, 0.39 mmol) was added at ambient temperature. The mixture was refluxed for 10 h. Cooled to ambient temperature, the precipitate was removed by filtration and the filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0030 g, y. 2.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.Cl>ClCCl.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)CC1(c2ccc(F)cc2)OC(=O)c2ccncc21
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CC1(c2ccc(F)cc2)OC(=O)C2=C1CNCC2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 53.2 %

Procedure:
To a solution of 3-(4-fluorophenyl)-3-isobutylfuro[3,4-c]pyridin-1(3H)-one (296 mg, 1.04 mmol) in dichloromethane (5 mL) at 0° C. was added 1 N HCl in diethyl ether. The reaction mixture was stirred at 0° C. for 40 min., then filtered and the precipitated hydrochloride salt dried in high vacuo for 1 hour. The precipitate was re-dissolved in ethanol (10 mL), PtO2 (40 mg) was added, and the reaction mixture was hydrogenated at 40 psi for 30 min. The mixture was filtered through a pad of diatomaceous earth, the filtrate concentrated in vacuo. The residue was re-dissolved in dichloromethane (50 mL) and stirred with sat. NaHCO3 soln. for 20 min., then dried (MgSO4) and concentrated. The residue was purified by column chromatography (4 g, SiO2, 0 to 2.5% methanol in dichloromethane) to provide 3-(4-fluorophenyl)-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (160 mg, 53%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.83-0.98 (m, 6H), 1.56 (br. s., 1H), 1.65 (ddd, J=13.37, 6.59, 5.27 Hz, 1H), 1.72-1.81 (m, 1H), 2.15-2.38 (m, 3H), 2.84-3.05 (m, 2H), 3.34-3.50 (m, 1H), 3.58-3.73 (m, 1H), 7.00-7.12 (m, 2H), 7.27-7.34 (m, 2H); MS m/z 290 (M+H)+, 288 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(O)C.[CH2:17]([CH2:19][NH2:20])[OH:18]>O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:20][CH2:19][CH2:17][OH:18])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: NCCO
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
25 g (0.123 mol) of 1-chloro-2,6-dinitrobenzene are placed in a three-necked, round-bottomed flask containing 180 ml of ethanol. The reaction mixture is heated to 70° C., 22.3 g (0.365 mol) of ethanolamine are added dropwise over 15 minutes and the mixture is left stirring at this temperature for 30 minutes. The temperature of the reaction mixture is left to return to room temperature and 1 liter of water is then added. The product crystallizes, is sucked dry, is washed with water and is dried. There are obtained 25 g of product which is used as is in the following stage.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][OH:6])=[O:4].[F:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][C:3]([NH:5][OH:6])=[O:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NCC(=O)NO
Reactant: O=S(=O)(Cl)c1ccc(OCCCCF)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CNS(=O)(=O)c1ccc(OCCCCF)cc1)NO
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the resin from stage 58.1 (350 mg, ˜0.3 mmol) are added successively 4-(4-fluorobutoxy)-benzenesulfonyl chloride (306 mg, 1.15 mmol) in dry dichloromethane (4 ml), and N-ethyldiisopropylamine (0.24 ml, 1.40 mmol) in dry dichloromethane (4 ml). After stirring for 15 h at r.t. the suspension is filtered and the resin washed with dichloromethane (2×), DMF (2×), alternating with H2O and DMF (3×), alternating with THF and 2-propanol (3×), dichloromethane (3×). The resin is dried under reduced pressure to provide polymer-bound 2-[4-(4-fluoro-butoxy)-benzenesulfonylamino]-N-hydroxy-acetamide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[CH:15]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][C:17]([N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=O.O>CCOCC>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[C:9]([C@@H:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][CH2:17][N:19]([CH:20]([CH3:22])[CH3:21])[CH:23]([CH3:24])[CH3:25])[CH:10]=1
Reactant: Cc1ccc(O)c(C(CC(=O)N(C(C)C)C(C)C)c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reaction time: 96 h
Yield: 20.9 %

Procedure:
A suspension of lithium aluminium hydride (3 g, 0.08 mols) in 350 ml of anhydrous ether is added with 0.5 g of 3-(2-hydroxy-5-methyl-phenyl)-N,N-diisopropyl-3-phenyl-propionamide in portions. The mixture is refluxed while stirring for 4 days. Afterwards, water is carefully added to destroy the lithium aluminium hydride excess, the mixture is acidified to pH 5 with acetic acid, the ether phase is separated and dried over sodium sulfate. The solvent is evaporated to obtain an oil which is purified by flash chromatography (eluent hexane-ethyl acetate 7:3). 0.1 g of tolterodine free base are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.C([O:18][N:19]=O)CCC.Cl>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:19][OH:18])[CH2:6]2
Reactant: CCCCON=O
Reactant: COc1ccc2c(c1C)CCC2=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1C)CC(=NO)C2=O
Reaction time: 0.5 h

Procedure:
To a solution of 5-Methoxy-4-methyl-indan-1-one (3.1 g) in MeOH at 40° C. was added n-butylnitrite (2.5 mL) followed by concentrated HCl (2.3 ml). The solution was stirred for 30 min during which time a precipitate was formed. The precipitate was collected and dried to yield the crude product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]=[O:22])[C:17]=3[CH:23]=2)[C:3]1=[O:24].[SH:25][CH2:26][CH2:27][CH2:28]O.[Bi](Cl)(Cl)Cl.C(#N)C>C(OCC)C>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]4[S:25][CH2:26][CH2:27][CH2:28][O:22]4)[C:17]=3[CH:23]=2)[C:3]1=[O:24]
Reactant: OCCCS
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Agent: Cl[Bi](Cl)Cl
Solvent: CC#N
Solvent: CCOCC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C4OCCCS4)c3c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (2.86 g, 8.05 mmol), 3-mercapto-1-propanol (0.600 ml, 6.84 mmol), bismuth (III) chloride (0.090 g, 0.285 mol) and acetonitrile is stirred overnight at room temperature. Additional 3-mercapto-1-propanol (0.200 ml, 2.31 mmol) and bismuth (III) chloride are added and the resultant mixture is concentrated in vacuo. The residue is chromatographed with ethyl acetate-hexanes to afford a solid, which is taken up in diethyl ether, washed with water, once with brine and dried over anhydrous magnesium sulfate. Concentration in vacuo affords the title compound as a white solid (1.15 g, 33.2%, mp 125-130° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([N:8]([CH:12]1[CH2:14][CH2:13]1)[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.C1(NCC2CC[O:23]CC2)CC1.C(NCC1CC1)C1C=CC=CC=1>C(Cl)Cl.CO>[CH:12]1([N:8]([CH2:1][CH:2]2[CH2:7][CH2:6][O:23][CH2:4][CH2:3]2)[C:9]([Cl:11])=[O:10])[CH2:14][CH2:13]1
Reactant: O=C(Cl)N(Cc1ccccc1)C1CC1
Reactant: C1CC(CNC2CC2)CCO1
Agent: c1ccc(CNCC2CC2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Cl)N(CC1CCOCC1)C1CC1

Procedure:
The title compound is prepared analogously as described for benzyl-cyclopropyl-carbamoyl chloride starting from cyclopropyl-(tetrahydro-pyran-4-ylmethyl)-amine (prepared analogously as described for benzyl-cyclopropylmethyl-amine). TLC, Rf (CH2Cl2/MeOH 95:5)=0.9.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([NH2:19])=[O:18].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](OC)=O)=[CH:23][CH:22]=1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[NH:19][C:17](=[O:18])[C:3]3[C:4]([CH3:16])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=3[N:1]=2)=[CH:23][CH:22]=1
Reactant: CCCCCCC(CC)n1nc(C)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc21
Yield: 34.7 %

Procedure:
10 mg (0.037 mmol) of 5-amino-3-methyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 45 mg (0.274 mmol) of methyl 4-aminophenylacetate are refluxed for 6 hours in 0.5 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 4.9 mg (35%) of a solid, Rf=0.45 (dichloromethane/methanol=15:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH2:16][CH3:17])=[N:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:18]1([Mg]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:18]1([CH:14]([C:12]2[C:11]([CH2:16][CH3:17])=[N:10][N:9]([C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)[CH:13]=2)[OH:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCc1nn(-c2cc(F)cc(F)c2)cc1C=O
Solvent: C1CCOC1
Product: CCc1nn(-c2cc(F)cc(F)c2)cc1C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution (10 mL) of 1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde (1.5 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (12.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.9 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:9]=[C:10](O)[C:11]3[CH2:16][O:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:26]>C(Cl)Cl>[Cl:26][C:10]1[C:11]2[CH2:16][O:15][CH2:14][C:12]=2[N:13]=[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:18])[N:9]=1
Reactant: Oc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Cl)cc1-c1nc(Cl)c2c(n1)COC2
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (100 mg, 0.36 mmol, 1 eq) in POCl3 (5 ml) was stirred under reflux for 1 h. The solution was then cooled to room temperature and concentrated under reduced pressure to give a white solid which was dissolved in dry methylene chloride. The solution was cooled to 0° C. and ice was added followed by sat. NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to provide a crude white solid which was purified by flash column chromatography (1:9 EtOAc:Hexane) to give 4-Chloro-2-(5-chloro-2-fluorophenyl)-5,7-dihydrofuro[3,4-d]-pyrimidine (78 mg, 73%) as a white solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[O:17]=[C:18]1[NH:23][C:22]([C:24]([O:26]CC)=O)=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[C:19]1=2.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:80]2[CH:84]=[N:83][C:82]([O:85][CH2:86][CH2:87][O:88][C:89]3[CH:90]=[C:91]([CH2:95][NH2:96])[CH:92]=[CH:93][CH:94]=3)=[N:81]2)C=CC=CC=1>>[O:17]=[C:18]1[NH:23][C:22]([C:24]([NH:96][CH2:95][C:91]2[CH:92]=[CH:93][CH:94]=[C:89]([O:88][CH2:87][CH2:86][O:85][C:82]3[N:83]=[CH:84][NH:80][N:81]=3)[CH:90]=2)=[O:26])=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[C:19]1=2
Reactant: CCOC(=O)c1nc2scc(-c3ccsc3)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccsc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 4-oxo-5-(3-thienyl)-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 65 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (48.0 mg, 34%).
Reaction SMILES: [Mg].[Cl-].[Ce+3].[Cl-].[Cl-].Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.CO[C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:26][C:25](=[O:27])[C:24]3=[CH:28][CH:29]=[CH:30][N:23]3[N:22]=2)=[CH:17][CH:16]=1>C1COCC1>[OH:31][C:14]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[NH:26][C:25](=[O:27])[C:24]4=[CH:28][CH:29]=[CH:30][N:23]4[N:22]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Reactant: BrCCCCBr
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(C3(O)CCCC3)cc2)nn2cccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 15 ml reaction vial is flushed with nitrogen and charged with dry THF (2.5 ml), magnesium turnings (55.5 mg, 2.28 mmol) and cerium(III) chloride (20.5 mg, 0.084 mmol). The suspension is cooled to 0° C., 1,4-dibromobutane (157 μl, 1.33 mmol) is added. The suspension is allowed to reach room temperature, stirred for 30 minutes at this temperature and again cooled to 0° C. Then, a solution of 4-(4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-benzoic acid methyl ester (113 mg, 0.42 mmol) in THF (1 ml) is added dropwise. The reaction mixture is stirred for 30 minutes at room temperature. The reaction mixture is quenched with saturated ammonium chloride solution and partitioned between ethyl acetate and water. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-[4-(1-hydroxy-cyclopentyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as white solid; HPLC/MS 1.75 (C), [M+H] 296; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 11.92 (s, 1H), 7.98-7.89 (m, 2H), 7.67 (dd, J=2.7, 1.7 Hz, 1H), 7.65-7.59 (m, 2H), 6.94 (dd, J=4.3, 1.7 Hz, 1H), 6.60 (dd, J=4.3, 2.6 Hz, 1H), 4.94 (s, 1H), 1.95-1.85 (m, 6H), 1.83-1.74 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:27](=[O:28])[CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)Cc1ccccc1
Product: CCc1noc(-c2sc(NC(=O)Cc3ccccc3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and phenyl-acetyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[F:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])=[N:3][CH:4]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP) (58.34 mg, 0.118 mmol), (2-methoxyphenyl)boronic acid (35.9 mg, 0.236 mmol), Pd(AmPhos)2Cl2 (8.36 mg, 0.012 mmol), potassium phosphate (75 mg, 0.354 mmol), 1,4-dioxane (443 μl), and water (148 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min h at 90° C. LC/MS showed conversion to the protected product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH and concentrated, and the crude product was purified by chromatography on silica gel (12-g column, 3% MeOH/DCM) to give 4-fluoro-1-(2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (49 mg, 0.118 mmol, 100% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.99 (br. s., 1H), 8.70 (d, J=1.7 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.99 (dd, J=1.8, 8.9 Hz, 1H), 7.78 (dd, J=1.8, 8.8 Hz, 1H), 7.58-7.50 (m, 1H), 7.38-7.27 (m, 2H), 7.23 (d, J=8.3 Hz, 1H), 7.16-7.10 (m, 1H), 6.89 (d, J=4.6 Hz, 1H), 3.65 (s, 3H); m/z (ESI) 416.2 (M+H)+.