Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([O-:5])=O.C(N(CC)C(C)C)(C)C.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([F:24])([F:33])[F:34])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Reactant: Nc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)OCc1ccccc1)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
A solution of mono-benzyl malonate (890 mg, 4.6 mmol) in 3:1 CH2Cl2/DMF (24 mL) was treated sequentially with N,N-diisopropylethylamine (2.0 mL, 11.5 mmol), 2-trifluoromethyl-phenylamine (0.6 mL, 4.6 mmol), and HATU (2.1 g, 5.5 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-(2-trifluoromethyl-phenyl)-malonamic acid benzyl ester as an oil (894 mg, 57% yield). This material was dissolved in EtOAc (35 mL). The resultant solution was charged with 10% Pd/C (178 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo to provide N-(2-trifluoromethyl-phenyl)-malonamic acid (621 mg, 95% yield). A portion of this material (100 mg, 0.4 mmol) was combined with [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (150 mg, 0.4 mmol, prepared as described in WO PCT 0250019) and dissolved in 6 mL of 3:1 CH2Cl2/DMF. The resultant solution was charged sequentially with N,N-diisopropylethylamine (0.35 mL, 1.5 mmol) and HATU (182 mg, 0.48 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide {(2S,3S)-3-hydroxy-2-[2-(2-trifluoromethyl-phenylcarbamoyl)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (54 mg, 28% yield). MS found: (M+Na)+=514.5.
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:35])[CH:10]([CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11](O)=O)[CH3:7].C=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:6]([O:8][C:9](=[O:35])[C:10]([CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(C(=O)O)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: ClCCl
Product: C=C(C(=O)OCC)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Diethylamine (0.52 mL, 5.04 mmol) was added to a mixture of 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-malonic acid monoethyl ester (1.7 g, 4.1 mmol) and 37% aq. solution of formaldehyde (0.42 mL, 5.6 mmol) in methylene chloride (6.5 mL) at 0° C. The mixture was stirred overnight at room temperature and then diluted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate and is brine and dried. After filtration and evaporation in vacuo the crude product was purified by flash chromatography (CH2Cl2) to yield 2-[(6-tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-acrylic acid ethyl ester (0.36 g, 23%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])[S:6][CH:7]=1.[CH3:20][NH:21][O:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+].CCO>O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][C:9](=[O:10])[NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:21]([O:22][CH3:23])[CH3:20])[N:4]=1
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1
Reactant: CNOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Yield: 86 %

Procedure:
A mixture of Intermediate 4: 2-(3-(3-fluorobenzyl)ureido)-4-chloromethyl-thiazole (40 g, 0.133 mol), N,O-dimethylhydroxylamine (80 g, 0.820 mol), sodium carbonate (40 g, 0.754 mol), and abs. EtOH (0.2 L) was stirred and heated at 60-70 C for 8-12 hours. The mixture was diluted with water (0.8 L) and cooled to 20 C with continued stirring. The solids were collected by filtration, washed with water, and dried in vacuo to afford the title compound (37 g, 86% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([O:12][CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[N:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)CCC>[CH3:13][O:12][C:9]1[C:8](=[O:14])[N:7]([CH3:15])[C:6]2[N:5]=[CH:4][N:3]=[C:2]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:20][CH2:21]3)[C:11]=2[N:10]=1
Reactant: COc1nc2c(Cl)ncnc2n(C)c1=O
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
4-Chloro-6-methoxy-8-methylpteridin-7(8H)-one (4.00 g, 17.7 mmol, 1 equiv) and 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (3.83 g, 17.7 mmol, 1 equiv) were suspended in anhydrous n-butanol (40 mL) in a 250 mL one-necked round-bottomed flask. Triethylamine (35.30 mmol, 3.57 g, 4.92 mL, 2 equiv) was added to the flask, and the stirred reaction mixture was heated to 80° C. The reaction was monitored by LC/MS and was complete after 6 hours. The resulting tan colored suspension was cooled to room temperature and filtered. The collected solid was washed with n-butanol (10 mL) and anhydrous ether (25 mL). The solid was air-dried to give the desired material, 6-methoxy-8-methyl-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one as a pale yellow colored solid (5.69 g, 79% yield.). 1H NMR (400 MHz, DMSO-d6): δ 10.83 (broad s, 1H), 8.33 (s, 1H), 7.13 (m, 1H), 6.93 (m, 3H), 5.30 (d, 1H), 4.54 (1H), 3.88 (s, 3H), 3.55 (s, 3H), 3.20 (t, 2H), 2.42 (dq, 2H), 1.82 (d, 2H). MS (EI) for C20H21N7O3: 408 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:11]O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].S(Cl)([Cl:15])=O>>[Cl:15][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: CS(=O)(=O)c1cccc(CO)c1
Reactant: O=S(Cl)Cl
Product: CS(=O)(=O)c1cccc(CCl)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of (3-methanesulfonyl)phenyl methanol (0.21 g, 1.1 mmol) in thionyl chloride (3 mL) was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to provide 1-chloromethyl-3-methanesulfonylbenzene as a yellow oil (0.23 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.59 (t, J=8 Hz, 1H), 4.65 (s, 2H), 3.08 (s, 3H)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[N:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1cccc(OCC(F)(F)F)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a stirred solution of methyl 6-(2,2,2-trifluoroethoxy)picolinate (0.40 g, 1.69 mmol, Step-2) in THF (17 mL) is added slowly lithium aluminum hydride (0.096 g, 2.53 mmol) at 0° C. The resulting mixture is stirred at rt for 1 hour. The reaction mixture is carefully quenched with 25% aqueous ammonia solution at 0° C. Then the mixture is diluted with DCM (50 mL) and celite is added to the mixture. After stirring at rt for 1 hour, the mixture is filtrated through a pad of celite, and the filtrate is concentrated in vacuo to give 0.32 g (92% yield) of the title compound as white solid. This material is used for the next reaction (Step-4) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4](O)=[O:5].Cl>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: OCc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
The required [2,6-dichloro-4-(trifluoromethyl)-phenyl]methanol was prepared as follows: To a solution of 1,3-dichloro-5-(trifluoromethyl)benzene (4.73 g; 22 mmol) in THF (40 mL) was added n-BuLi in hexanes (8 mL; 2.50 mol/l; 20 mmol), at −78° C. The resulting mixture was stirred for 15 minutes and poured onto dry ice in THF. The reaction mixture was acified to pH=3 (with 5 M aqueous HCl solution) and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 8:2) to afford 2,6-dichloro-4-(trifluoromethyl)benzoic acid (1.2 g). To a solution of this 2,6-dichloro-4-(trifluoromethyl)benzoic acid (1.7 g; 6.6 mmol) in THF (20 mL) was added dropwise a solution of borane-THF complex in THF (1 mol/1, 13.3 mL; 13.3 mmol). Subsequently, the resulting mixture was stirred overnight at 60° C. To the reaction mixture was added 1 M aqueous HCl (30 mL), at 0° C., and the resulting mixture was stirred at RT for 10 minutes. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% aqueous NaHCO3-solution. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:3 followed by Et2O:hexanes 1:1) to afford [2,6-dichloro-4-(trifluoromethyl)phenyl]-methanol (1.3 g), which was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH2:14][CH:13]=[C:12]([CH3:15])[CH2:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].CC(C)([O-])C.[K+].Cl.[Cl-].[Na+]>CS(C)=O.C1(C)C=CC=CC=1>[CH3:8][C:2]([C:9]1[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC1=CCC(C(C)(C)CCC(=O)O)=CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CC1=CC=C(C(C)(C)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
A mixture of 4 -methyl-4(4-methyl-1,4-cyclohexadien-1-yl)pentanoic acid (45.3 g, 0.22 mol), potassium t-butoxide (102 g, 0.91 mmol), toluene (110 ml) and dimethyl sulfoxide (1,000 ml) was stirred for 24 hours at room temperature. The solution was cooled, brought to neutral pH with hydrochloric acid, poured into 2 liters saturated sodium chloride, and extracted with methylene chloride. After the solution was washed with saturated sodium chloride solution and the solvent removed, the residual oil was distilled to yield 41.3 g (65.2%) of the 4-methyl-4(4-methyl-1,3-cyclohexadien-1-yl) pentanoic acid: bp 136°-138° (1 mm); nD20 1.5029; δmax 264 nm; δTMSCDCl3 11.15 (s,1), 5.62 (s,2), 2.06 (s,4) 1.78 (s,3), 1.05 (s,6).
Reaction SMILES: C([O:4][CH2:5][C:6]1[S:7][CH2:8][C:9]([CH2:12][Cl:13])(O)[N:10]=1)(=O)C.C(OCC)C>Cl.C(O)(C)C>[ClH:13].[Cl:13][CH2:12][C:9]1[N:10]=[C:6]([CH2:5][OH:4])[S:7][CH:8]=1
Reactant: CC(=O)OCC1=NC(O)(CCl)CS1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: OCc1nc(CCl)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
7.48 g of 2-acetoxymethyl-4-chloromethyl-4-hydroxy-thiazoline, prepared according to either Example 3 or 4, was suspended in 20 ml of 5N hydrogen chloride in isopropanol and heated to reflux for 45 minutes. The suspension was cooled in an ice bath and 30 ml of diethyl ether added dropwise over 30 minutes. The slurry was stirred a further 30 minutes at 0° C. and the precipitate filtered, washed with ether and dried under vacuum. 4-chloromethyl-2-hydroxymethylthiazole hydrochloride, 6.22 g (93% yield) was obtained.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]/[C:6](Cl)=[O:7])[CH3:2].[NH2:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][C:15]2[NH:16][C:17](=[O:28])[C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH3:24][N:23]1[C:18]2[C:17](=[O:28])[NH:16][C:15]([CH2:14][C:13]3[CH:29]=[CH:30][C:10]([NH:9][C:6](=[O:7])/[CH:5]=[CH:4]/[O:3][CH2:1][CH3:2])=[CH:11][CH:12]=3)=[N:20][C:19]=2[C:21]([CH2:25][CH2:26][CH3:27])=[N:22]1
Reactant: CCO/C=C/C(=O)Cl
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Solvent: c1ccncc1
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(=O)/C=C/OCC)cc3)nc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(E)-3-ethoxyacryloyl chloride (J. Chem. Soc; 1958,153) (298 mg, 0.0022 mol), was added dropwise to an ice-cooled solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (600 mg, 0.002 mol) in pyridine (15 ml) and the reaction stirred at room temperature for 20 hours. The mixture was partitioned between water (30 ml) and dichloromethane (30 ml), the aqueous layer acidified to pH1 with 2M aqueous hydrochloric acid solution and then extracted with dichloromethane (2×40 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure, to give, after recrystallisation from ethyl acetate/methanol the title compound (483 mg), m.p.241-243° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:6]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:21]([NH:23][C@H:24]([C:26]5[N:31]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[C:30](=[O:38])[C:29]6=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]6[N:27]=5)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=4[N:16](COCC[Si](C)(C)C)[CH:15]=3)=[N:10]2)[CH:8]=1.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])[CH:6]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:21]([NH:23][C@H:24]([C:26]5[N:31]([C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=6)[C:30](=[O:38])[C:29]6=[C:39]([CH3:42])[CH:40]=[CH:41][N:28]6[N:27]=5)[CH3:25])=[N:20][CH:19]=[N:18][C:17]=4[NH:16][CH:15]=3)=[N:10]2)[CH:8]=1
Reactant: COc1cc(NS(C)(=O)=O)cc(-n2ccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)n2)c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccn(-c6cc(O)cc(NS(C)(=O)=O)c6)n5)c34)n(-c3ccccc3)c(=O)c12
Yield: 66 %

Procedure:
(S)—N-(3-Methoxy-5-(3-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-pyrazol-1-yl)phenyl)methanesulfonamide (15 mg, 0.01 mmol) was treated with boron tribromide (1M in dichloromethane, 1 ml, 1 mmol) in dichloromethane (1 ml) and then with a solution of ammonia (7N in methanol, 10 ml, 70 mmol) according to the method described in Example 41 to give 4.2 mg (44% yield) of the title compound. Purity 92%.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([P:16]([O:21][CH2:22][CH3:23])(=[O:20])[O:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)(OCC)=O)C.[H-].[Na+].[CH:26]([C:28]1[CH:37]=[CH:36][C:35]2[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=2[CH:29]=1)=O.Cl>CS(C)=O>[CH3:38][C:34]1([CH3:39])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]2[CH:29]=[C:28](/[CH:26]=[CH:9]/[C:10]3[CH:11]=[CH:12][C:13]([P:16]([O:17][CH2:18][CH3:19])(=[O:20])[O:21][CH2:22][CH3:23])=[CH:14][CH:15]=3)[CH:37]=[CH:36][C:35]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Reactant: CCOP(=O)(Cc1ccc(P(=O)(OCC)OCC)cc1)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOP(=O)(OCC)c1ccc(/C=C/c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
A solution of 22 g (53 millimoles) of diethyl 4diethylphosphonomethylbenzenephosphonate in 100 ml of dimethyl sulfoxide was added dropwise to a suspension of 1.8 g (64 millimoles) of sodium hydride in 50 ml of dry dimethyl sulfoxide at room temperature. Stirring was continued for 1 hour, after which a solution of 8.7 g (40 millimoles) of 2-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene in 75 ml of dimethyl sulfoxide was added dropwise. Stirring was continued for 16 hours at room temperature and the mixture was poured onto water, acidified with 2N hydrochloric acid and extracted three times with ether. The combined organic phases were washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulfate and evaporated down. The residue was purified by column chromatography (silica gel; heptane/0.55 - 10% ethyl acetate) to give 5.5 g of the title compound of melting point 83°-84° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:37]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([CH2:35][C:36]([C:38]4[CH:39]=[CH:40][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:42][CH:43]=4)=[O:37])[CH2:26][CH2:27]3)=[C:15]2[CH:14]=[N:13]1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(CC(=O)c5ccc(OC(F)(F)F)cc5)CC4)ncnc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 10 mL round-bottomed flask fitted with a N2 inlet was placed a stir bar, 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (43 mg, 0.11 mmol), K2CO3 (138 mg, 1 mmol) and DMF(1 mL). 2-Bromo-1-(4-trifluoromethoxy-phenyl)-ethanone (30 mg, 0.1 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 30 minutes. The resulting suspension was filtered and concentrated under vacuum. The crude was purified by preparative HPLC to give Compound A94. 1H NMR (CDCl3, 400 MHz) δ 2.43 (m, 2H), 2.59 (m, 2H), 3.14 (s, 3H), 3.68 (m, 2H), 3.78 (m, 2H), 4.78 (s, 2H), 5.81 (m, 1H), 7.35 (d, 2H), 7.96 (m, 3), 8.01 (m, 2H), 8.42 (s, 1H), 8.65 (s, 1H). Exact mass calculated for C26H23F4N5O5S 593.14, found 594.3 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:12])=O)=[CH:4][CH:3]=1.C(#N)C.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]#[N:12])=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1-c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: N#Cc1ccccc1-c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Add 2-(4-iodophenyl)benzamide (4.45 g, 0.0138 moles, preparation 56), acetonitrile (45 mL), and triethylamine (2.93 grams, 0.0289 moles) to a 100 mL 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, ice-water bath, and addition funnel. Cool the contents of the 100 mL 3-neck round-bottom flask to 0° C. Add trifluoroacetic anhydride (3.04 grams, 0.0145 moles) to the reaction mixture via the addition funnel over 5 minutes. Observe a temperature increase to about 24° C., and cool the reaction mixture to 0° C. Stir the reaction mixture for 60 minutes. Add water (45 mL) and stir the suspension at ambient temperature for 60 minutes. Collect the precipitate by filtration and rinse the filter cake with water. Vacuum (15-25 mm) dry the filter cake at 50° C. to provide the title compound (4.03 g, 0.0132 moles) in 95.9% yield. 1H NMR(CDCl3, 500.0 MHz): δ 7.82 (app. d, 2H, J=9); 7.75 (dd, 1H, J=1.5, 8); 7.63 (dt, 1H, J=1.5, 7.5); 7.46 (d, 1H, J=8); 7.45 (dt, 1H, J=1.5, 7.5); 7.28 (app. d, 2H, J=8.5).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[CH3:42][NH:43][CH3:44].[BH4-].[Na+]>CO>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:41]=[CH:40][C:37]([CH2:38][N:43]([CH3:44])[CH3:42])=[CH:36][CH:35]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:10][CH2:11]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CNC
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 4.9 %

Procedure:
A mixture of 4-(9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.15 mmol) and 27% dimethylamine solution (62 mg, 0.44 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium borohydride (8.3 mg, 0.22 mmol) was added. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (4.2 mg, yield 5%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.73-0.79 (m, 4H), 1.84 (m, 1H), 2.69 (s, 6H), 3.47-3.72 (m, 8H), 4.14 (s, 2H), 4.31-4.33 (d, J=8.0 Hz, 1H), 7.12-7.35 (m, 9H), 7.47-7.58 (m, 2H); LC-MS (ESI) m/z: 577 (M+1)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.O.CO>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[N:13][CH:14]=1
Reactant: CCOC(=O)C1CCN(c2ccc(F)cn2)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2ccc(F)cn2)CC1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 5′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (12.5 g, 0.0495 mol) in THF (60 mL), H2O (60 mL) and MeOH (6 mL) was added LiOH.H2O (2.6 g, 0.0172 mol). Stirring was continued overnight at RT before the organic solvent were removed under vacuo. The pH of the was adjusted to 5 with acetic acid, and the white precipitate was filtered off and dried to yield 9.2 g (83%) of 5′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid. ES-MS m/e: 223.1 (M−H+)