Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[N+:4]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]=1[NH:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])([O-])=O>C(O)(=O)C>[NH2:4][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]=1[NH:18][C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCCC(C)C)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(NC(=O)CCCC(C)C)c1
Yield: 25.4 %

Procedure:
A solution of 2.00 g of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide was added dropwise to a slurry of 0.428 g of 60% sodium hydride and 10 ml of N,N-dimethylformamide at room temperature, and the mixture was stirred for 30 minutes. A solution of 1.46 g of isopropyl iodide in 10 ml of N,N-dimethylformamide was then added dropwise thereto, and the mixture was stirred at 100° C. for 5 days. The reaction solution was poured into a mixed solution of 80 g of dilute hydrochloric acid and 80 g of ethyl acetate for separation. The resulting organic layer was washed with 50 g of water, and was then concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 4:1) to obtain 0.260 g of crude ethyl 4-nitro-3-(N-i-propylbutyrylamino)benzoate. Subsequently, 3 ml of ethanol and 2 ml of acetic acid were added to 0.260 g of ethyl 4-nitro-3-(N-i-propylbutyrylamino)benzoate at room temperature, and 0.519 g of reduced iron were further added thereto. The mixture was heat-refluxed for 4 hours. The solid material was removed using a filtration aid, and the filtrate was concentrated. The residue were added 30 ml of ethyl acetate and 30 ml of dilute hydrochloric acid for separation. The organic layer was washed with 30 ml of water, and was then concentrated under reduced pressure. The residue was purified through preparative thin-layer silica-gel chromatography (developing eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1) to give 0.06 g of ethyl 4-amino-3-(N-i-propylbutyrylamino)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:5]([C:6]([OH:8])=O)[CH:4]=1.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:5]([C:6]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:8])[CH:4]=1
Reactant: COc1cc(C(=O)O)nc2ccc([N+](=O)[O-])cc12
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccc([N+](=O)[O-])cc12

Procedure:
4-Methoxy-6-nitroquinaldic acid (1 g) and N,N' -carbonyldiimidazole (0.7 g) in dimethylformamide (25 ml) were heated on a steam bath for 1 hour. 5-Aminotetrazole (0.7 g) was added and the mixture was heated for 30 minutes on a steam bath. 4-Methoxy-6-nitro-N(1H-tetrazol-5-yl)quinaldamide, m.p. 308° was filtered off.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:41]=[CH:40][N:39]([CH3:42])[C:38](=[O:43])[CH:37]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:36]3[CH:41]=[CH:40][N:39]([CH3:42])[C:38](=[O:43])[CH:37]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Cn1ccc(Br)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Yield: 50.9 %

Procedure:
A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (50 mg, 0.11 mmol) and 4-bromo-1-methylpyridin-2(1H)-one (30 mg, 0.16 mmol), Pd(Ph3P)2Cl2 (10 mg), and aq. Cs2CO3 solution (4 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated to reflux for 2 h. When the reaction was over, the mixture was washed with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (25 mg, 51%). 1H NMR (CDCl3): δ=1.35 (m, 1H), 1.47 (d, 3H), 1.63 (m, 2H), 1.94 (m, 2H), 2.18 (m, 1H), 2.39 (m, 2H), 2.86 (m, 1H), 3.51 (m, 5H), 5.63 (m, 1H), 6.31 (m, 1H), 6.70 (m, 1H), 6.91 (m, 2H), 7.20-7.32 (m, 8H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-nitrobenzyl alcohol (6 g, 39 mmoles) is put into solution in dichloromethane (100 ml) and carbon tetrabromide (14.9 g, 45 mmoles) is added. Triphenylphosphine (11.8 g, 45 mmoles) is added in portions to the medium at 0° C. Then the mixture is agitated for 2 hours at ambient temperature. The solvent is evaporated off and the product obtained is purified on silica gel in an ethyl acetate/heptane mixture (1/2). It is obtained in the form of white needle-shaped crystals (7.2 g; 85%). Melting point: 97-98° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[C:11](=[O:12])[NH:10][N:9]=[CH:8]2)[S:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C)C=O>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:10]2[C:11](=[O:12])[N:7]([C:5]3[S:4][C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([CH3:1])[CH:6]=3)[CH:8]=[N:9]2)=[CH:27][CH:26]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)cc1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A mixture of ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate (0.15 g, 0.59 mmol), potassium carbonate (0.16 g, 1.19 mmol) and 4-fluorobenzyl bromide (0.11 mL, 0.90 mmol) in N,N-dimethylformamide (3 mL) was stirred at 80° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature, then partitioned between ethyl acetate (75 mL) and water (35 mL). The organic layer was washed with brine (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 0-40% ethyl acetate in hexanes to afford the title compound as a cream solid in 81% yield (0.17 g): 1H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H), 7.42-7.36 (m, 2H), 7.08-7.01 (m, 2H), 6.93 (s, 1H), 4.98 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 362.2 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:13]([NH2:15])[CH3:14].C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[Cl:2][C:3]1[C:8]([C:9]([F:11])([F:12])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:13]([NH:15][C:45]([C:41]1[CH:40]=[C:39]2[C:44](=[CH:43][CH:42]=1)[N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([C:24]3[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:34][CH:33]=1)[C:37]([CH3:49])=[C:38]2[CH3:48])=[O:46])[CH3:14]
Reactant: C[C@H](N)c1cccc(C(F)(F)F)c1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(F)(F)F)c3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-chloro-3-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 605 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([C@@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2C(OC(C)(C)C)=O)[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]4[C@H:29]([CH3:30])[CH2:28][C@@H:27]([OH:31])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:17][CH2:16]2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CO.Cl.O1CCOCC1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([C@@H:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)[C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[C:22]4[C@H:29]([CH3:30])[CH2:28][C@@H:27]([OH:31])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:19][CH2:20]2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(C(F)(F)F)c(F)c4)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(C(F)(F)F)c(F)c4)[C@@H]4CCCN4)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
(S)-tert-Butyl 2-((S)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (0.040 g, 0.066 mmol) was dissolved in dichloromethane (4 mL) and MeOH (1 mL) and treated with HCl in dioxane (2 mL, 8.0 mmol). The mixture was stirred at ambient temperature overnight. The reaction was concentrated in vacuo to produce the desired product (0.033 g, 99% yield). MS (APCI+) [M+H] 508.1; 2.13 minutes.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH:12]3[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:40]=[C:39]3[C:35]([CH2:36][C:37](=[O:41])[NH:38]3)=[CH:34][CH:33]=2)O1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:19]1[CH:18]=[C:17]([CH:12]2[N:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:6]([C:2]([C:32]5[CH:40]=[C:39]6[C:35]([CH2:36][C:37](=[O:41])[NH:38]6)=[CH:34][CH:33]=5)=[CH:3][N:4]=4)[N:7]=3)[CH2:16][CH2:15][O:14][CH2:13]2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C3)OC1(C)C
Reactant: Fc1cccc(C2COCCN2c2ccc3ncc(Br)n3n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1Cc2ccc(-c3cnc4ccc(N5CCOCC5c5cccc(F)c5)nn34)cc2N1
Temperature: 150 °C
Reaction time: 20 h

Procedure:
In step 2-6, a suspension of 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-3-(3-fluorophenyl)morpholine (25 mg, 0.067 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (34 mg, 0.13 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.7 mg, 0.0033 mmol) in 3 mL of 1,4-dioxane and 0.5 mL of 2.0M sodium carbonate was bubbled with nitrogen and heated to 150° C. and stirred for 20 hours. The solution was cooled to room temperature and purified with HPLC to afford 6-(6-(3-(3-fluorophenyl)morpholino)imidazo[1,2-b]pyridazin-3-yl)indolin-2-one (2-6) as a white solid.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[N:17])=[C:5]([Cl:18])[N+:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>CO>[Cl-:18].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[N:17])=[C:5]([NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[N+:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCNc1cc(N)[n+](CCCCCC)c(Cl)c1C#N
Reactant: CCCCN
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCCCNc1cc(N)[n+](CCCCCC)c(NCCCC)c1C#N
Yield: 61 %

Procedure:
3.37 gms (.01 mole) of 2-amino-6-chloro-5-cyano-1-n-hexyl-4-n-hexylamino pyridinium chloride (compound II - Table 1) was dissolved in methanol and 1.0 gm (0.01 mole) of triethylamine and 0.8 gms (0.011 mole) of n-butylamine added. The solution was refluxed for 1 hour and on cooling 2.5 gms (60% yield) of 2-amino-6-n-butylamino-5-cyano-1-n-hexyl-4-n-hexylamino pyridinium chloride (compound 42 - Table 2) crystallised out. [m.p. 179° - 180°C. c 64.88 (64.6) H 9.81 (9.78) N17.11 (17.1)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([NH2:28])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]([NH2:28])=[S:43])=[CH:15][CH:14]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=O)ccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Yield: 144.8 %

Procedure:
To a suspension of 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (4.05 g, 9 mmol) in toluene (50 ml) was added Lawesson's reagent (2.19 g, 5.4 mmol), and the mixture was refluxed under heating for 1 h. The reaction mixture was purified by silica gel column chromatography to give tert-butyl[6-(aminothiocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (3.64 g, 86.9%) as crystals.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)[OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:22][C:2]([F:1])([F:21])[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(OCc1ccccc1)N1CCC(C(O)C(F)(F)F)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(C(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1.00 g (83.15 mmol) of benzyl 4-(2,2,2-trifluoro-1-hydroxyethyl)piperidine-1-carboxylate and 4.95 g (11.66 mmol) Dess-Martin periodinane in 30 mL of DCM was stirred for 20 hours at RT and then made alkaline with saturated aqueous potassium carbonate solution. The reaction mixture was filtered and the phases of the filtrate were separated. The organic phase was dried over sodium sulfate and evaporated down in vacuo. Yield: 896 mg (90% of theoretical); C15H16F3NO3 (M=315.288); calc.: molpeak (M−H)−: 314; found: molpeak (M−H)−: 314; Rf value: 0.39 (silica gel, cyc/EtOAc 2: 1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:10])C=O)=[CH:3][CH:2]=1.[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])CCC1C=CC=CC=1Cl)([CH3:14])([CH3:13])[CH3:12].ClC1C=CC=CC=1C=CC=O>>[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH2:10][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C=O)c1ccncc1
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Agent: O=CC=Cc1ccccc1Cl
Product: CC1CCN(C(=O)C(CCc2ccncc2)NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-4-ylpropyl}carbamate is prepared from pyridin-4-yl propionaldehyde (Kitbunnadaj, R. et al. J. Med. Chem, 2004, 47, 2414-2417) in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is prepared from 3-(2-chlorophenyl)propenal in Example 5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:27]2[CH2:28][CH2:29][C@@H:25]([F:24])[CH2:26]2)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: F[C@@H]1CCNC1
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CC[C@@H](F)C2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following similar methods to those described in Preparation 352 starting from (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester and (R)-3-fluoro-pyrrolidine. MS: [M+H]+=392.
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:9]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:10][CH:11]=[CH2:12])[O:5][P:6](Cl)Cl)#[N:2].C[Si](C)(C)[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C1(C)C=CC=CC=1>[C:1]([CH2:3][CH:4]([C:9]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:10][CH:11]=[CH2:12])[O:5][P:6]([C:20]1[NH:19][CH:23]=[CH:22][N:21]=1)[C:20]1[NH:21][CH:22]=[CH:23][N:19]=1)#[N:2]
Reactant: C=CCC(CC)(CC)C(CC#N)OP(Cl)Cl
Reactant: C[Si](C)(C)n1ccnc1
Solvent: Cc1ccccc1
Product: C=CCC(CC)(CC)C(CC#N)OP(c1ncc[nH]1)c1ncc[nH]1
Reaction time: 0.17 h

Procedure:
To toluene (3 ml) there were added 0.578 g (2.05 mmol) of 2-cyano-1-(1,1-diethyl-3-butenyl)ethoxydichlorophosphine and 0.632 g (4.50 mmol) of 1-(trimethylsilyl)imidazole under an argon atmosphere at room temperature, and reaction was conducted for 10 minutes. After by-product chlorotrimethylsilane and toluene were removed under reduced pressure for 25 minutes at room temperature, the residual toluene and excess 1-(trimethylsilyl)imidazole were removed under reduced pressure for 2 hours at 55° C. to obtain 2-cyano-1-(1,1-diethyl-3-butenyl)ethoxybisimidazolyl phosphine as a colorless transparent oil. This was dissolved in 4.1 ml of a mixed solution of chloroform-d and chloroform, and the solution (0.5 M) was added at −3.5° C. under an argon atmosphere to 1.414 g (2.15 mmol) of N6-benzoyl-5′-O-(4,4′-dimethoxytrityl)-2′- deoxyadenosine that had been subjected to azeotropic dehydration with 5 ml of 1,4-dioxane at room temperature for one hour. Upon reaching homogeneity, the mixture was allowed to stand overnight at 4° C. for reaction to obtain the target nucleotide derivative. The 31P NMR {external standard: (CH3O)3P=140 ppm, CDCl3} was δ; 129.5, 130.3, 131.1, 134.3 ppm (measuring the 31P NMR spectrum with a 161.7 MHz NMR measuring apparatus).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)C>[CH2:15]([NH:22][C:2]1[C:3]2[S:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: Clc1ncnc2c1sc1ccccc12
Solvent: CC(C)O
Product: c1ccc(CNc2ncnc3c2sc2ccccc23)cc1
Yield: 68.6 %

Procedure:
4-Chlorobenzothieno[3,2-d]pyrimidine (111 mg, 0.5 mmol), (see following experimental) and benzylamine (114 mg, 1.0 mmol) (111 mg, 1.1 mmol) in stirred 2-propanol (2 mL) are heated at reflux under N2 for 26 h. The mixture is allowed to cool, and the precipitate is collected by Buchner filtration, rinsed with 2-propanol and water and dried in an oven to give 4-benzylaminobenzothieno[3,2-d]pyrimidine (100 mg, 68%) as a white powder. 1H NMR (DMSO) δ8.60 (1H, s), 8.51 (1H, t, J=5.9 Hz), 8.31 (1H, ddd, J=0.7, 1.4, 8.0 Hz), 8.17 (1H, ddd, J=0.7, 1.8, 8.1 Hz), 7.68 (1H, ddd, J=1.2, 7.0, 8.1 Hz), 7.59 (1H, ddd, J =1., 7.0, 8.1 Hz), 7.36 (2H, d, J=7.4 Hz), 7.33 (2H, t, J=7.3 Hz), 7.24 (1H, t, J=7.2 Hz), 4.79 (2H, d, J=6.0 Hz).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[C:15]1([CH2:14][CH2:13][CH2:12][N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol), 3-bromo-propyl-benzene (0.119 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.100 g, 80%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.99 (m, 2H), 2.66 (t, 2H), 3.68 (t, 2H), 4.38 (s, 2H), 7.18-7.56 (m, 8H), 7.92 (d, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.Br[CH2:12][C:13]1[N:14]([CH3:29])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[N:18]=[C:17]([Cl:28])[N:16]=2>>[Cl:28][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[C:13]([CH2:12][N:1]3[CH2:6][CH2:5][CH:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]3)[N:14]2[CH3:29])=[C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:18]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Yield: 93.2 %

Procedure:
2-(Piperidin-4-yl)propan-2-ol (0.73 g) was reacted with 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (1.6 g) via General Procedure C to yield 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (1.76 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3N=C(CSC4C=CC=CC=4)S[CH:18]=3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[NH2:27][C:28](=[S:41])[C:29]([CH3:40])([CH3:39])[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[N:27]=[C:28]([C:29]([CH3:39])([S:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)(=[O:32])=[O:31])[CH3:40])[S:41][CH:18]=3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C(N)=S)S(=O)(=O)c1ccccc1
Reactant: COc1ccc2cc(-c3csc(CSc4ccccc4)n3)c(=O)[nH]c2c1
Solvent: CO
Product: COc1ccc2cc(-c3csc(C(C)(C)S(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Temperature: 120 °C

Procedure:
This compound was prepared according to the procedure described for Example 8836(c) by employing 3-(2-bromo-acetyl)-7-methoxy-1H-quinolin-2-one (Example 8741, 250 mg, 0.84 mmol) and 2-amino-1,1-dimethyl-1-(phenylsulfonyl)ethane-2-thione (Step b, 1.7 mL, 1.0 mmol) in 3.5 mL of anhydrous MeOH was heated at 120° C. for 3×5 min by microwave synthesizer. The reaction mixture was cooled to RT. The precipitates were collected by filtration and washed with MeOH and CH2Cl2 to provide the title compound as a white solid. MS m/z: 441 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[CH:17][CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:20][C:21]1[C:22]([NH2:28])=[N:23][CH:24]=[N:25][C:26]=1Cl.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[NH2:28][C:22]1[N:23]=[CH:24][N:25]=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[CH:17][CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[C:21]=1[Br:20]
Reactant: C[C@H](N)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: Nc1ncnc(Cl)c1Br
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1Br)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 71.1 %

Procedure:
(S)-2-(1-Aminoethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (1.2 g, 4.72 mmol) was treated 5-bromo-6-chloropyrimidin-4-amine (2 g, 9.6 mmol), cesium fluoride (1.44 g, 9.48 mmol), N,N-diisopropylethylamine (4.2 mL, 24.11 mol) according to Preparation 13. The residue was purified by flash chromatography using Isolera® Purification System (0% to 50%, dichloromethane-ethyl acetate) to give 1.43 g (71% yield) of the title compound as a solid. Purity 100%.