Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[F:14][C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:15]=3[F:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1cc(C(F)(F)F)ccc1F
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3cc(C(F)(F)F)ccc3F)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-fluoro-5-trifluoromethyl-benzylamine (124 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (132 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-fluoro-5-trifluoromethyl-benzylamino)-2H-phthalazin-1-one: 27 mg (12.5%): m/z (M+H)=372. 1H-NMR (DMSO-d6) δ: 12.38 (s, 1H), 7.95 (d, 1H), 7.85 (m, 1H), 7.75 (m, 1H), 7.65 (m, 1H), 7.49 (m, 1H), 7.19 (dd, 1H), 6.87 (s, 1H), 4.56 (d, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:34])[CH2:37][CH2:36]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5(O)CC5)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A170) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C@H:49]([OH:52])[CH2:50][OH:51])[CH2:44][CH2:43]2)=[CH:38][C:37]=1[O:53][CH3:54]>COCC(O)C>[CH3:54][O:53][C:37]1[CH:38]=[C:39]([CH:42]2[CH2:43][CH2:44][N:45]([CH2:48][C@H:49]([OH:52])[CH2:50][OH:51])[CH2:46][CH2:47]2)[CH:40]=[CH:41][C:36]=1[NH:35][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Reactant: COc1cc(C2CCN(C[C@H](O)CO)CC2)ccc1N
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(C[C@H](O)CO)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 100 °C
Yield: 26.6 %

Procedure:
Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (320.00 mg, 0.857 mmol), N,N-Diisopropylethylamine (0.779 mL, 4.47 mmol), and (S)-3-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-propane-1,2-diol (600.65 mg, 2.142 mmol) were dissolved in 1-methoxy-2-propanol (2.3 mL) and the reaction mixture was heated at 100° C. for 8 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous NaHCO3, and the organic layer was separated and dried over MgSO4, then filtered. The solvent was evaporated under reduced pressure and the product was isolated by column chromatography (ISCO, Silicagel, methanol/dichloromethane 0-10%). The product needed to be further purified by preparative reverse phase HPLC (Gilson, 0.1% TFA water/acetonitrile gradient) followed by neutralization of the resulting TFA salt to afford (S)-3-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-propane-1,2-diol as a light orange solid (115 mg, 27%). MP: 66-80° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.99 (dd, J=8.0, 1.6 Hz, 1H), 7.44 (m, 2H), 7.13 (m, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.02 (d, J=4.7 Hz, 1H), 6.83 (d, J=4.7 Hz, 1H), 6.72 (s, 1H), 6.71 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.86 (m, 1H), 3.85 (s, 3H), 3.77 (m, 1H), 3.55 (m, 1H), 3.22 (d, J=10.6 Hz, 1H), 3.08 (d, J=10.6 Hz, 1H), 2.77 (br s, 2H), 2.69 (m, 1H), 2.48 (m, 3H), 2.20 (m, 1H), 1.85 (m, 4H); LC/MS (ESI+): 504.19 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][O:19][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: Nc1cccc2ncccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Nc2cccc3ncccc23)cc1
Temperature: 100 °C
Reaction time: 170 h

Procedure:
5-Aminoquinoline (14.4 g, 0.10 mol), methyl 4-bromobenzoate (21.6 g, 0.10 mol), Cs2CO3 (45.6 g, 0.14 mol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.96 g, 1.5 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.44 g, 0.5 mmol) were mixed in toluene (15 ml) and stirred at 100° C. for 170 h. At the end of this time the reaction mixture was screened and the filtrates were evaporated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with a (1:1) mixture of hexane and ethyl acetate. The elute was collected and the solvent was removed under reduced pressure to yield the product (contaminated with a small amount of 5-aminoquinoline) which was used in the next stage without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])(=[O:22])=[O:21])[CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[S].[CH2:32](N)[CH2:33][NH2:34]>>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([CH2:19][NH:18][CH2:17][CH2:16][CH2:15][N:13]([CH3:14])[C:11](=[O:12])[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:34][CH2:33][CH2:32][N:2]=2)=[CH:8][CH:7]=1)(=[O:22])=[O:21]
Reactant: NCCN
Reactant: CN(CCCNCS(=O)(=O)c1cccc(Cl)c1Cl)C(=O)CCc1ccc(C#N)cc1
Agent: [S]
Product: CN(CCCNCS(=O)(=O)c1cccc(Cl)c1Cl)C(=O)CCc1ccc(C2=NCCN2)cc1

Procedure:
Analogously to 13b), N-{3-[(2,3-dichlorobenzenesulphonyl)methylamino]propyl}-3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylpropionamide was prepared from 0.7 g (1.49 mmol) of 3-(4-cyanophenyl)-N-{3-[(2,3-dichlorobenzenesulphonyl)methylamino]propyl}-N-methylpropionamide, 0.1 g (3.12 mmol) of sulphur and 3 ml of ethylenediamine.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].B1([O-])O[O:17]1.O.O.O.O.[Na+]>C(O)(=O)C>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])[C:1]([OH:17])=[O:2])#[N:9]
Reactant: CC[C@@H](C)Oc1ccc(C=O)cc1C#N
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC[C@@H](C)Oc1ccc(C(=O)O)cc1C#N
Temperature: 50 °C
Yield: 93.9 %

Procedure:
To a solution of 5-formyl-2-{[(1R)-1-methylpropyl]oxy}benzonitrile (D37) (310 mg, 1.53 mmol) in acetic acid (30 ml) was added sodium perborate tetrahydrate (471 mg, 3.05 mmol), the reaction mixture was heated at 50° C. over the weekend. The reaction mixture was concentrated in vacuo and water (˜50 ml) added, EtOAc (˜30 ml) was added and the layers partitioned, the aq layer was extracted twice more with EtOAc (˜30 ml) and the combined organics evaporated to dryness under reduced pressure to give the title compound (315 mg) as an off-white solid. δH (d6-DMSO, 400 MHz): 8.07-8.24 (2H, m), 7.38 (1H, d), 4.63-4.77 (1H, m), 1.55-1.83 (2H, m), 1.31 (3H, d), 0.95 (3H, t). MS (ES+): C12H13NO2 requires 219; found 220 (MH+).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)#[N:3]>C(OCC)(=O)C>[N:15]1([C:12]2[S:13][CH:14]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:2]#[N:3])[N:11]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(C#N)c3)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2csc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.3 %

Procedure:
A 4 N solution (25 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(3-cyanophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (920 mg, 2.48 mmol) in ethyl acetate (50 ml), the mixture was stirred at room temperature for 6 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 438 mg (65.2%) of the desired product as a solid.
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[C:9](=[N:10][S:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(O)CCC>[C:15]([NH:19][CH2:14][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:13]2[C:9](=[N:10][S:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: c1cc(OCC2CO2)c2nsnc2c1
Reactant: CC(C)(C)N
Solvent: CCCCO
Product: CC(C)(C)NCC(O)COc1cccc2nsnc12
Yield: 57 %

Procedure:
12.5 g (60 mM) 4-(2,3-epoxypropyloxy)-2,1,3-benzthiadiazole were dissolved in 150 ml. n-butanol and, after the addition of 40 ml. tert.-butylamine, heated under reflux for 3 hours. When the reaction was finished, the reaction mixture was evaporated and the residue was chromatographed on a silica gel column in the manner described in Example 1. There were obtained 9.6 g (57% of theory) 4-(3-tert.-butylamino-2-hydroxy-propyloxy)-2,1,3-benzthiadiazole, which had a melting point of 89°-91° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:18][CH2:19]Cl)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:31])[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][N:22]([CH3:31])[C:23]1[NH:24][CH:25]=[C:26]([CH2:19][CH2:18][N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:27]=1[N+:28]([O-:30])=[O:29]
Reactant: CN(C)c1[nH]ccc1[N+](=O)[O-]
Reactant: ClCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1[nH]cc(CCN(Cc2ccc(Cl)cc2)Cc2ccc(Cl)nc2)c1[N+](=O)[O-]

Procedure:
This compound was prepared in a manner analogous to that set forth in Step G of Example 1, using 0.47 gram (0.0014 mole) of [(6-chloro(3-pyridyl)methyl](2-chloroethyl)[(4-chlorophenyl)methyl]amine (prepared in Steps A and B of the present Example), 0.2 gram (0.0013 mole) of dimethyl(3-nitropyrrol-2-yl)amine and 0.45 gram (0.0032 mole) of potassium carbonate in 20 mL of DMF. The crude product was purified with column chromatography on silica gel. Elution was accomplished using 50% hexane in diethyl as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.05 gram of Compound 214. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=4[CH3:30])[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Cu]Cl>[CH3:30][C:24]1[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[N:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([C:35]4[CH:36]=[N:37][C:32]([CH3:31])=[CH:33][CH:34]=4)=[N:7][CH:6]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: Cc1cccc(-n2nc3c4ccccc4n(Cc4ccc(Br)nc4)nc-3c2=O)c1C
Reactant: Cc1ccc(B(O)O)cn1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(Cn3nc4c(=O)n(-c5cccc(C)c5C)nc-4c4ccccc43)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-[(6-Bromopyridin-3-yl)methyl]-2-(2,3-dimethylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (0.10 g, 0.22 mmol), (6-methylpyridin-3-yl)-boronic acid (74 mg, 0.54 mmol, 2.5 equiv), palladium(II)acetate (9.7 mg, 0.043 mmol, 0.2 equiv), 1,1′-bis(diphenylphosphino)ferrocene (24 mg, 0.043 mmol, 0.2 equiv), copper(I)chloride (21 mg, 0.22 mmol, 1 equiv) and cesium carbonate (0.18 g, 0.54 mmol, 2.5 equiv) were combined in N,N-dimethylformamide (4 mL) and placed into an oil bath preheated to 100° C. for 60 minutes. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (20 mL, aqueous saturated) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound as a deep red solid: 1H-NMR (400 MHz, CDCl3) δ 9.06 (1H, d, J=2.1 Hz), 8.78 (1H, d, J=1.7 Hz), 8.32 (1H, dd, J=7.8, 1.0 Hz), 8.19 (1H, dd, J=8.1, 2.3 Hz), 7.77 (1H, dd, J=8.3, 2.4 Hz), 7.72 (1H, d, J=8.3 Hz), 7.65-7.54 (3H, m), 7.42-7.38 (1H, m), 7.30-7.22 (3H, m), 5.90 (2H, s), 2.61 (3H, s), 2.37 (3H, s), 2.20 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 473.2099 [(M+H)+; calculated for C29H25N6O: 473.2084].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[F:8][C:9]1[C:14](O)=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:8][C:9]1[C:14]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)CCCBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCCBr)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
To a solution of 4-bromobutyric acid (0.91 g, 5.4 mmol), pentafluorophenol (1.00 g, 5.4 mmol) and DMAP (0.13 g, 1.1 mmol) in CH2Cl2 (10 ml) cooled to 0° C. under nitrogen, N,N-dicyclohexylcarbodiimide (1.70 g, 8.1 mmol) was added in portions. After 1 h the reaction was slowly warmed to room temperature and stirred for 5 hours. The dicyclohexylurea was filtered off and the mother liquor was concentrated and purified by flash chromatography (n-Hexane/EtOAc 98:2) affording 4-bromobutyric acid pentafluorophenyl ester as a colourless oil (1.40 g, 78%). A mixture of 4-bromobutyric acid pentafluorophenyl ester (0.65 g, 1.9 mmol) and AgNO3 (0.83 g, 4.9 mmol) in CH3CN (8 ml) was warmed at 70° C. for 20 minutes at the microwave. The formed salts were filtered off, the solvent was concentrated and the residue purified by flash chromatography (n-Hexane/EtOAc 95:5) affording 4-nitrooxybutyric acid pentafluorophenyl ester as a clear oil (0.38 g, 62%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]1[C:20](=O)[CH2:19][CH2:18][C:17]([C:22](OC)=[O:23])=[CH:16]1>>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:22][OH:23])[CH2:16]1
Reactant: COC(=O)C1=CN(c2c(C)cccc2C)C(=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cccc(C)c1N1CCCC(CO)C1
Reaction time: 2 h

Procedure:
In an atmosphere of nitrogen, a 1.0 M diisobutylaluminum hydride THF solution was dropwise added at −78° C. to a THF solution of methyl 1-(2,6-dimethylphenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate. After stirring at −78° C. for 2 hours, the temperature was risen to 0° C., followed by stirring at 0° C. for 1.5 hours. The reaction mixture was warmed up to room temperature, followed by stirring at room temperature for 2 hours. A 1.0 M diisobutylaluminum hydride THF solution was dropwise added to the reaction mixture at 0° C., followed by warming up to room temperature and stirring for 1 hour to obtain methyl 1-(2,6-dimethylphenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate. In an atmosphere of nitrogen, lithium aluminum hydride was added to the resulting methyl 1-(2,6-dimethylphenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate, while cooling on an ice-methanol bath. Thereafter, by stirring the reaction mixture for 2 hours while heating under reflux, [1-(2,6-dimethylphenyl)piperidin-3-yl]methanol was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22]C3CCCCO3)[C:5]=2[O:4][CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[OH:22][C:21]1[C:5]2[O:4][CH2:3][C:2](=[O:1])[N:7]([CH2:8][CH2:9][O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1COc2c(OC3CCCCO3)cccc2N1CCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: O=C1COc2c(O)cccc2N1CCOCc1ccccc1
Yield: 80 %

Procedure:
3-oxo-4-(2-(benzyloxy)ethyl)-8-(tetrahydropyrane-2-yloxy)-3,4-dihydro-2H-1,4-benzoxazine (1.89 g) was dissolved in methanol (100 ml), and pyridinium p-toluenesulfonate (126 mg) was added to the resultant solution, and the mixture was refluxed for 12 hours. The solvent was distilled off under reduced pressure, and the residue was poured into a saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate. The resultant organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (silica gel:hexane/ethyl acetate=1/1) to obtain the object compound (1.18 g, yield 80%).
Reaction SMILES: Br[C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[O:4][C@H:3]1[N:13]1[CH:20]=[C:19]([CH3:21])[C:17](=[O:18])[NH:16][C:14]1=[O:15].C([O-])(=O)C.[Na+].[H][H]>CO.S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O>[C:10]([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:13]2[CH:20]=[C:19]([CH3:21])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:2][C@@H:6]1[OH:7])(=[O:12])[CH3:11]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](Br)[C@@H]1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Yield: 38.1 %

Procedure:
12.47 g (28.1 mmol) of 2'-deoxy-2'-bromo-5'-O-acetyl-5-methyluridine were dissolved in 240 ml of methanol, and 6.91 g (3 equivalents) of sodium acetate were added thereto. To the reaction mixture, were added 1.25 g of 5% palladium-barium sulfate catalyst (0.1 equivalent). Then, the reaction system was filled with hydrogen gas and reacted for 24 hours at room temperature. The catalyst was removed from the reaction mixture, 100 ml of water were added, and the reaction mixture was neutralized to have a pH of 7.0 by adding an aqueous 25% sodium hydroxide solution thereto. The resulting solution was concentrated to about 100 ml, sodium chloride was added thereto until saturation, and the thus-saturated solution was extracted with ethyl acetate. The thus-extracted organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain white crystals. The crystals were washed with a small amount of methylene chloride to obtain 3.04 g (10.7 mmol) of 5'-O-acetylthymidine. Its yield was 38.1%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[CH2:26]([S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30])[CH2:27][CH3:28].C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:35]3[CH2:34][CH2:33][N:32]([S:29]([CH2:26][CH2:27][CH3:28])(=[O:30])=[O:31])[CH2:37][CH2:36]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CCCS(=O)(=O)N1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol), 1-(propylsulfonyl)piperazine hydrochloride (144 mg, 0.75 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (40-55% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (111.6 mg, 89%). 1H NMR (DMSO-d6) δ: 10.87 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.16 (s, 1H), 6.16 (s, 1H), 4.32 (t, J=5.3 Hz, 2H), 4.00 (t, J=5.9 Hz, 2H), 3.53 (t, J=5.3 Hz, 2H), 3.36-3.45 (m, 2H), 2.90 (s, 3H), 2.37 (s, 3H), 1.95-2.15 (m, 2H), 1.45 (s, 6H); ESI-MS: m/z 501.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[Cl:7].[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]2[C:29]3[CH:28]=[N:27][CH:26]=[N:25][C:24]=3[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=2)=[O:20])[CH:16]=[N:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([C:19]([C:21]3[C:29]4[CH:28]=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=3)=[O:20])[CH:14]=2)=[O:11])[C:6]=1[Cl:7]
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cn1cnc(Cl)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cn3cnc(Cl)c3Cl)c2)c2cncnc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
(4,5-Dichloro-imidazol-1-yl)-acetic acid (25.2 mg, 0.130 mmol) was added to (5-amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (28.1 mg, 0.1 mmol), HATU (49.4 mg, 0.130 mmol) and DIPEA (51.7 uL, 0.300 mmol) in anhydrous DMF (1 mL). The mixture was stirred at 50° C. for 16 hours and then evaporated in vacuo and purified by prep-HPLC (method 5) to afford the title compound in 46% yield, 21.2 mg.