Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([S:19][CH2:20][CH2:21][NH2:22])[N:16]=[C:15]([NH2:23])[N:14]=2)[C:10]([CH3:24])=[CH:9][C:8]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32]([NH:34][CH:35]([CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(C(N)C(O)=O)CN.Cl.Cl.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([S:19][CH2:20][CH2:21][NH:22][C:36](=[O:37])[CH:35]([NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:39][CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:16]=[C:15]([NH2:23])[N:14]=2)[C:10]([CH3:24])=[CH:9][C:8]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cc(C)c(-c2cc(SCCN)nc(N)n2)cc1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCCC(N)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2cc(SCCNC(=O)C(CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)nc(N)n2)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[2-Amino-6-(2-aminoethylsulfanyl)pyrimidin-4-yl]-2,4-dimethylbenzoic acid tert-butyl ester (1.9 g, 5.10 mmol) obtained in Step 1 above, DL-2,4-bis((tert-butoxycarbonyl)amino)butyric acid (which can be prepared from commercially available DL-2,4-diaminobutyric acid dihydrochloride by the method described in Journal of Inorganic Biochemistry (2004) 98(11): 1933-1946) (4.9 g, 15.3 mmol), and 1-hydroxybenzotriazole (2.1 g, 15.3 mmol) were dissolved in N,N-dimethylformamide (40 ml). 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.9 g, 15.3 mmol) and diisopropylethylamine (3.6 ml, 20.4 mmol) were added to the solution, and stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (400 ml), and then sequentially washed with a saturated aqueous sodium bicarbonate solution (300 ml), water (300 ml, three times), and a saturated aqueous sodium chloride solution (300 ml). After the organic layer was dried over anhydrous sodium sulfate (50 g), the inorganic salt was filtered and washed with ethyl acetate. The filtrate and washing solution were combined together, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=40:1) to yield 5-{2-amino-6-[2-(2,4-bis-tert-butoxycarbonylaminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2,4-dimethylbenzoic acid tert-butyl ester (3.2 g) as a white solid material.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[NH3:25]>C(#N)C>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH2:25])[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: N
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(N)n2)cc1
Reaction time: 18 h

Procedure:
A solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (2 g, 5.258 mmol) in acetonitrile (30 ml) was treated with 0.880 ammonia (6 ml) dropwise. The resulting mixture was then stirred at 20 C. for 18 h. This gave the title compound as a colourless precipitate which was collected by filtration and dried (1.53 g)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=O)[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:16][CH2:17]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]([CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1nc(C(=O)NCC2CC2)nc2c1[nH]c(=O)n2Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CC2Nc3c(N)nc(C(=O)NCC4CC4)nc3N2Cc2ccccc2)cc1
Temperature: 55 °C
Yield: 28.5 %

Procedure:
6-Amino-9-benzyl-N-(cyclopropylmethyl)-8-oxo-8,9-dihydro-7H-purine-2-carboxamide (Example 1, 50 mg, 0.15 mmol) was taken up in 3 ml DMA and firstly triethylamine (27 μl, 0.18 mmol) and then para-methoxybenzyl chloride (26 μl, 0.18 mmol) were added in one portion each and the whole stirred and heated to 55° C. for 16 h. The mixture was diluted with ethyl acetate (5 ml) and washed with water (2×3 ml). The combined organics were dried over MgSO4 and concentrated in vacuo to a yellow residue which was purified by column chromatography using a gradient of 100% DCM:→98:2 DCM:MeOH as the eluant. Combination and evaporation of the appropriate fractions provided the title compound as a white solid (19 mg).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[CH2:3][O:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([O-:18])=[O:17])=[CH:14][CH:13]=2)[N:8]=[C:7]([NH:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=2)[N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:2]([F:1])([F:35])[CH2:3][O:4][C:5]1[N:6]=[C:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=2)[N:8]=[C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Nc3ccc(C(=O)[O-])cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Nc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of crude tert-butyl 4,4′-(6-(2,2,2-trifluoroethoxy)-1,3,5-triazine-2,4-diyl)bis(azanediyl)dibenzoate (562 mg) in CH2Cl2 (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 16 hours. All solvents were removed under vacuum. The residue was purified by preparative HPLC to give 4,4′-(6-(2,2,2-trifluoroethoxy)-1,3,5-triazine-2,4-diyl)bis(azanediyl)dibenzoic acid (110 mg).
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[CH2:20][NH:21][CH3:22])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(OC)=[O:2].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]2[CH2:11][CH:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:1](=[O:2])[N:21]([CH3:22])[CH2:20][C:13]=2[CH:14]=1
Reactant: CNCc1cc(OC)ccc1CC(CC(=O)OC)C(=O)OC
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1Cc2ccc(OC)cc2CN(C)C1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 93.9 %

Procedure:
A solution of methyl (±)-3-carbomethoxy-4-[2-(methylamino)methyl-4-methoxyphenyl]butanoate (11.06 mmole) and diisopropylethylamine (5.8 mL, 33.18 mmole) in toluene (110 mL) was heated at reflux for 25 hr, stirred at RT for 4 days, then heated at reflux for another 24 hr. Concentration and silica gel chromatography (5% MeOH in 1:1 EtOAc/CHCl3) gave the title compound (2.88 g, 94%) as a light yellow solid: TLC (5% MeOH in 1:1 EtOAc/CHCl3) Rf 0.63; 1H NMR (250, CDCl3) δ 7.02 (d, J=8.4 Hz, 1 H, 6.78 (dd, J=8.4, 2.7 Hz, 1 H), 6.63 (d, J=2.7 Hz, 1 H), 5.29 (d, J=16.3 Hz, 1 H), 3.50-3.90 (m, 2 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 2.73-3.16 (m, 3 H), 3.04 (s, 3 H), 2.41 (dd, J=16.7, 5.4 Hz, 1 H; MS (ES) m/e 300 (M+Na)+, 278 (M+H)+.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2.[OH2:37]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][C:31](=[O:37])[NH:32]2
Reactant: c1ccc(-c2cccc3[nH]ccc23)nc1
Reactant: O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccccn2)N1
Reaction time: 1 h
Yield: 92 %

Procedure:
Pyridinium tribromide (90% (Aldrich), 15.4 g, 43.2 mmol) was added portion-wise over 10 minutes to a suspension of 4-pyridin-2-yl-1H-indole (2.8 g, 14.4 mmol) in 2-methyl-2-propanol (84 mL), ethanol (56 mL) and acetic acid (28 mL). The mixture was stirred at room temperature for 2 hours after which acetic acid (100 mL) was added. Stirring was continued for one hour and then water (0.5 mL) and zinc dust (9.4 g, 144 mmol) were added. Stirring was continued for another hour. Residual zinc dust was filtered and washed with methanol. The filtrate was concentrated and the syrupy residue was stirred in water(300 mL) overnight. The solid that formed was filtered, washed with water to remove zinc and pyridine salts and dried under high vacuum to give 2.8 g (92%) of 4-pyridin-2-yl-1,3-dihydroindol-2-one was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: ClCc1nc2ccccc2o1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2nc3ccccc3o2)c(=O)[nH]c1=O
Yield: 43.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (176 mg, yield: 43.2%).
Reaction SMILES: O1CCN(C(CCC(O)=O)=O)CC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:31]1[CH2:36][CH2:35][N:34]([C:37]([CH2:39][CH2:40][N:41]=[C:42]=[O:43])=[O:38])[CH2:33][CH2:32]1.[F:44][C:45]1[C:46](=[O:52])[NH:47][C:48](=[O:51])[NH:49][CH:50]=1>C1C=CC=CC=1.C(N(CC)CC)C>[O:31]1[CH2:32][CH2:33][N:34]([C:37]([CH2:39][CH2:40][NH:41][C:42]([N:49]2[CH:50]=[C:45]([F:44])[C:46](=[O:52])[NH:47][C:48]2=[O:51])=[O:43])=[O:38])[CH2:35][CH2:36]1
Reactant: O=C=NCCC(=O)N1CCOCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C(O)CCC(=O)N1CCOCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCNC(=O)n1cc(F)c(=O)[nH]c1=O)N1CCOCC1

Procedure:
The reaction of 3-morpholinocarbonylpropionic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 2-morpholinocarbonylethyl isocyanate, which was reacted with 5-fluorouracil to provide 1-[N-(2-morpholinocarbonylethyl)carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 4.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CS(C)=O.[OH:11][C:12]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]2[CH:32]=[CH:31][CH:27]([CH2:28]CO)[C:26]([CH3:34])([CH3:33])[CH:25]=2)=[O:23])[CH2:15][CH2:14]1.OOS([O-])=O.[K+]>C(Cl)Cl.O.C(N(CC)CC)C>[OH:11][C:12]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]2[CH:32]=[CH:31][C:27]([C:26]([CH3:33])([CH3:34])[CH:2]=[O:3])=[CH:28][CH:25]=2)=[O:23])[CH2:17][CH2:18]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)C=C(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)C=CC1CCO
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C=O)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: -55 °C
Reaction time: 0.25 h

Procedure:
Dissolve oxalyl chloride (1.57 g, 12.4 mmol) in methylene chloride (17 mL), cool to -55° C. and place under a nitrogen atmosphere. Add, by dropwise addition, a solution of dimethylsulfoxide (1.77 g, 1.61 mL) in methylene chloride (4.5 mL). Stir for 15 minutes and add, by dropwise addition, a solution of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethyl alcohol (5.0 g, 10.3 mol) in methylene chloride (33 mL). Stir for 30 minutes and add, by dropwise addition, triethylamine (7.2 mL). Stir for 15 minutes and then allow to warm to -10° C. Add a solution of oxone (12.66 g) in deionized water (50 mL). Stir for 15 minutes and add methylene chloride (25 mL). Separate the organic phase, wash with brine, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (ethyl acetate) to give 4-[4-[4-(hydoxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetaldehyde.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:29]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:30])=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(OCCN2CCCC2)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (2.15 g, 10.42 mmol) and triethylamine (3.27 mL, 23.4 mmol) in 100 mL methylene chloride at 0° C. was added cyclohexanecarbonyl chloride (1.46 mL, 10.94 mmol), dropwise. The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with 50 mL methylene chloride. The combined organic layers were dried (magnesium sulfate), filtered, and concentrated to afford the title compound of Step A. MS 317.2 (M+1)+
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:11]1([CH:9]([OH:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CCc1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
β-Phenylpropiophenone (6-1) (7.5 g, 36.0 mmol) was suspended in ethanol (100 ml) and sodium borohydride (0.68 g, 18.0 mmol) was added under N2. The resulting solution was stirred at ambient temperature overnight. The ethanol was removed in vacuo and the residual oil-solid was taken up in ethyl acetate (100 ml) and water (30 ml). The ethyl acetate layer was removed, washed with water, dried, filtered and concentrated in vacuo to give 6-2 as a colorless oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH3:40])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:22]=[C:21]([NH:23][CH2:24][CH:25]3[C:30]([F:32])([F:31])[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:26]3)[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[CH:14]=2)=[CH:9][CH:8]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:32][C:30]1([F:31])[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:26][CH:25]1[CH2:24][NH:23][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][N:19]=2)[CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([N:6]([CH2:5][CH2:4][OH:3])[CH3:40])=[CH:12][CH:11]=2)[N:22]=1
Reactant: CCOC(=O)CN(C)c1ccc(-c2cc3nccnc3c(NCC3CN(C(=O)OC(C)(C)C)CCC3(F)F)n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CCO)c1ccc(-c2cc3nccnc3c(NCC3CN(C(=O)OC(C)(C)C)CCC3(F)F)n2)cc1
Yield: 22.5 %

Procedure:
A solution of tert-butyl 3-((7-(4-((2-ethoxy-2-oxoethyl)(methyl)amino)phenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)-4,4-difluoropiperidine-1-carboxylate (120 mg, 0.21 mmol) and LiAlH4 (10 mg, 0.25 mmol) in 5 mL of THF at 0° C., under N2, was stirred at 0° C. for 1 hour. The volatiles were removed in vacuo, and the residue was purified by chromatography with MeOH/H2O (1:8˜5:1) to give 25 mg of title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>CN(C)C(=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCOc1ccc([N+](=O)[O-])c(CO)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
5.1 g (30 mmol) of 5-hydroxy-2-nitrobenzyl alcohol were stirred with 2.5 g (18 mmol) of potassium carbonate and 25 ml of N,N-dimethylacetamide at 70°-80° C. for 30 minutes. After cooling to 20° C., 3.9 ml (36 mmol) of 1-butylbromide were added dropwise and the mixture was stirred at 90° C. for 2 hours. After cooling, the reaction mixture was concentrated in vacuo, the residue was treated with water and the pH was brought to 7 with 2N HCl. The oil obtained crystallizes after about 30 minutes; the product was filtered off with suction, washed with water and dried; 6 g, melting point 47°-49° C.
Reaction SMILES: [C:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si](C)(C)C.[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18]>>[C:1]1([CH:7]([NH2:10])[CH2:8][C:9]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccccc2)N1
Reactant: CC(C)(C)O
Agent: C[Si](C)(C)Cl
Product: CC(C)(C)OC(=O)CC(N)c1ccccc1
Yield: 47 %

Procedure:
A solution of 10 g of 4-phenylazetidin-2-one and 15.2 g of chlorotrimethylsilane in 150 cm3 of anhydrous tert.-butanol are refluxed for 7 days. The solution is then evaporated and ethyl acetate and aqueous sodium bicarbonate at 5% are added. The organic phase is washed with water, dried on sodium sulphate and is then evaporated. 7 g of tert.- butyl 3-phenyl-3-amino-propanoate are obtained (yield 47%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: CO
Reactant: O=C(O)c1cc(F)ccc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)ccc1F
Temperature: 60 °C

Procedure:
To a stirred solution of 2,5-difluorobenzoic acid (20 g, 126 mmol) in MeOH (250 mL) is added thionyl chloride (22.5 g, 190 mmol) dropwise at ice-cold conditions. After complete addition the reaction mixture is heated at 60° C. for 3 h. The reaction mixture is concentrated and the residue neutralized with aqueous Na2CO3 solution. It is extracted with CH2Cl2 (3×100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford the desired 2,5-difluorobenzoic acid methyl ester as a thick liquid (22 g).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C1(=O)O[CH2:14][CH2:13][O:12]1.[OH-].[Na+].C1(C)C=CC=CC=1>CN(C=O)C>[OH:12][CH2:13][CH2:14][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=C1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCO
Reaction time: 2 h

Procedure:
Adenine (9.1 g), ethylene carbonate (6.0 g), and sodium hydroxide (0.14 g) in DMF (68 ml) were heated at reflux for 2 hr. The solution was cooled to 0°, then 70 ml of toluene were added. After sitting for 2 hr at 0°, the precipitate was collected, rinsed with 100 ml of toluene, then cold ethanol, and dried to afford N9 -hydroxyethyladenine.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH3:14])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:17]([O:24][CH2:25][C@H:26]([NH:30]C(OC(C)(C)C)=O)[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH2:30][C@@H:26]([CH2:25][O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:27]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][C:9]=1[CH3:14])=[O:28]
Reactant: Cc1cc(Oc2ccc(F)cc2)ccc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: Cc1cc(Oc2ccc(F)cc2)ccc1NC(=O)[C@@H](N)COCc1ccccc1
Yield: 58 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)-2-methylaniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)-2-methylphenyl)propanamide (613 mg, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[N:6][C:7]=1F.Cl.[NH:33]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41](=[O:50])[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:35][CH2:34]1>>[Br:1][C:2]1[C:7]([N:33]2[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41](=[O:50])[O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:35][CH2:34]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCCNCC1)OCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Agent: Cl
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(N3CCC[C@@H](NC(=O)OCc4ccccc4)CC3)n2)c2cc(-c3cccnc3)ncc21

Procedure:
Following the procedures of Examples 241 and 287, 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-benzyl azepan-4-ylcarbamate hydrochloride were reacted to give (R)-benzyl 1-(3-bromo-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate, which was dissolved in Trifluoroacetic Acid (5 mL) and Methylene chloride (5 mL), and treated with Trifluoromethanesulfonic acid (5 eq.) and Triethylsilane (5 eq.). The resulting mixture was stirred at room temperature for 2 days. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 313 as an off-white solid (14.2 mg, 25.5%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.24 (s, 2H), 8.91 (s, 1H), 8.61 (d, J=3.6 Hz, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.62-7.51 (m, 2H), 4.00 (d, J=14.6 Hz, 2H), 3.90-3.81 (m, 2H), 3.77 (dd, J=11.4, 6.7 Hz, 2H), 3.67-3.59 (m, 3H), 2.18 (s, 1H), 1.98 (dd, J=31.3, 18.3 Hz, 4H), 1.75-1.59 (m, 1H); ESI MS m/z=464.01 (M+1)
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:26][C:9]2[N:10]([CH3:25])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:19]1([CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]3[N:10]([CH3:25])[C:9]4[CH2:26][CH:6]([CH2:4][OH:3])[CH2:7][C:8]=4[C:16]=3[CH:15]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c2c(c3cc(OCc4ccccc4)ccc31)CC(CO)C2
Temperature: 70 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-7-phenylmethoxy-4-methycyclopent[b]indole-2-carboxylic acid ethyl ester (2.0 g, 0.006 mole) in 50 ml of dry tetrahydrofuran, was added lithium aluminum hydride (1M solution in tetrahydrofuran, 10 ml, 0.01 mole). After stirring at 70° C. for one hour, the mixture was cooled, quenched with 2 ml of saturated ammonium chloride solution, filtered, and the filtrate concentrated to a brown oil, ~2 g. This oil was eluted on a silica gel column with 10% methanol/dichloromethane via HPLC. The desired fractions were combined and concentrated to a tan oil, which solidified on standing to give 1.3 g of the product, m.p. 83°-85° C.