Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:5]1[CH2:10][C:9]([CH2:11][O:12]CC2C=CC=CC=2)=[N:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]1=[O:27])(=[O:3])[CH3:2]>CCO.[Pd]>[C:1]([N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:5]1[CH2:10][C:9]([CH2:11][OH:12])=[N:8][N:7]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:6]1=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(COCc2ccccc2)=NN(C(=O)OC(C)(C)C)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N(C(=O)OC(C)(C)C)N1CC(CO)=NN(C(=O)OC(C)(C)C)C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-(benzyloxymethyl)-3-oxo-5H-1,2,4-triazine-2-carboxylate (38.0 g, 79.7 mmol) in EtOH (400 mL) under argon atmosphere was added palladium on charcoal (dry, 5 wt % Pd, 8.00 g). The reaction mixture was purged with hydrogen and heated to 60° C. At this temperature, the reaction mixture was stirred 24 h under H2-atmosphere (approx. 1 atm). The mixture was purged with argon and then filtered using a short plug of silica gel followed by rinsing with additional EtOAc. Evaporation of the solvent furnished the desired product as a sticky oil. LCMS (Method I) RT 1.57 min. [M+H]+ 387.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[CH2:20]([O:19][C:17]([C:16](=[C:30]1[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:14]1[N:15]=[C:11]([NH:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[O:23])[S:12][CH:13]=1)=[O:18])[CH3:21]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2F)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2F)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.7 g of ethyl 2-(3-o-fluorophenylureido)thiazol-4-ylglyoxylate, 0.96 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:8]([CH2:10]OS(C)(=O)=O)[C:7]=2[CH:16]=1.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)=[O:21])[CH3:18].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:10][C:8]2[C:7]3[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:9]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1CCCNC1
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)=C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(CC2=Cc3ccc(OC)cc32)C1
Reaction time: 18 h

Procedure:
To a solution of 7.27 g (30 mmol) of methanesulphonic acid (5-methoxybenzocyclobuten-1-yl)methyl ester in 60 ml of dimethylformamide there are added first 5.66 g (36 mmol) of piperidine-3-carboxylic acid ethyl ester and then 9.70 g (75 mmol) of N-ethyl-N,N-diisopropylamine. The mixture is stirred at 60° for 18 hours and, after cooling, is concentrated by evaporation under a high vacuum. The residue is taken up in diethyl ether and washed with water, and the organic phase is extracted with 2N hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline at reduced temperature with concentrated sodium hydroxide solution and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated to dryness by evaporation under reduced pressure. 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]2[C:45](=[O:56])[C:46]3[C:51]([C:52]=2[CH:53]=1)=[CH:50][C:49]([O:54][CH3:55])=[CH:48][CH:47]=3>>[CH3:55][O:54][C:49]1[CH:48]=[CH:47][C:46]2[C:45]([C:35]3[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=3)[C@@H:8]3[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]3[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])([OH:56])[C:44]3[C:52]([C:51]=2[CH:50]=1)=[CH:53][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=O
Product: COc1ccc2c(c1)-c1cc(OC)ccc1C2(O)c1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]2O[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O

Procedure:
5-(3,6-Dimethoxy-9-hydroxyfluoren-9-yl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 3,6-dimethoxyfluoren-9-one (J. Org. Chem. (1993) 58 (16), 4398-4404) instead of benzophenone) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH2:17][OH:18]>CC#N.O=[Mn]=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH:17]=[O:18]
Reactant: O=C(CC(F)(F)F)NCc1ccc(Cl)c(CO)c1
Agent: O=[Mn]=O
Solvent: CC#N
Product: O=Cc1cc(CNC(=O)CC(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
MnO2 (1.44 g, 14.9 mmol) was added to a sol. of N-(4-chloro-3-hydroxymethyl-benzyl)-3,3,3-trifluoro-propionamide (841 mg, 2.99 mmol) in CH3CN (60 mL). The mixture was stirred at rt for 3 h. MnO2 (1.44 g, 14.9 mmol) was added again, and the mixture was stirred for 90 min. The mixture was filtered over Celite, and the precipitate was washed with CH3CN and CH2Cl2. The solvents were removed under reduced pressure, and the residue was dried under high vacuum, yielding the crude title compound (840 mg, quantitative yield) that was used without purification. LC-MS: tR=0.84 min; ES+: 341.21.
Reaction SMILES: Br/[C:2](=[CH:10]\[C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[N:13]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:12]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])/[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C.CCCCCC>C1(C)C=CC=CC=1>[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1/[C:2](=[CH:10]\[C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[N:13]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[C:12]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])/[C:3]([O:5][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:4]
Reactant: CCOC(=O)c1c(/C=C(\Br)C(=O)OC(C)(C)C)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(/C=C(/C(=O)OC(C)(C)C)c2ccco2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
Combine (Z)-2-bromo-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester (1.00 g, 1.6 mmol), furan-2-boronic acid (0.27 g, 2.4 mmol), and cesium carbonate (1.00 g, 3.2 mmol) in toluene (15 mL). Sparge with nitrogen for 15 minutes. Add tetrakis(triphenylphosphine)palladium(0) (50 mg). Heat to 90° C. After 3 days, partition the reaction mixture between ethyl acetate and water. Separate the layers. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a reside. Chromatograph the residue on silica gel eluting with 15% diethyl ether/hexane to give the title compound.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([CH:14]=[N:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1.[OH-].[Na+]>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]2[C:19]3[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][NH:15]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(C=NCCc2ccccc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(C2NCCc3ccccc32)cc1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
To a solution of trifluoromethanesulfonic acid (15.3 mL, 173 mmol) at 0° C. was added N-(4-chlorobenzylidene)-2-phenylethanamine (3.38 g) and the reaction was heated to 120° C. and stirred 17 h under N2. The reaction was poured into ice water (100 mL) and basisified with 5N NaOH (45 mL). The aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with saturated NaCl (100 mL), dried (MgSO4) and concentrated to give a yellow/brown oil. The residue was purified by ISCO (120 g SiO2, 0-50% EtOAc/hexane) to give 1-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([F:16])=[CH:14][NH:13][C:12](=[O:17])[CH:11]=2)[CH:3]=1.Br[CH:19]([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([F:16])=[CH:14][N:13]([CH:19]([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12](=[O:17])[CH:11]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1F
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: CC(C(=O)OC(C)(C)C)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
126 mg (0.51 mmol) of 4-chloro-2-(5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.05 eq. of tert-butyl 2-bromopropanoate (racemate) were reacted according to General Method 4B at 100° C. Yield: 48 mg (25% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:3]=1.[BH4-].[Na+].[Cl-].[NH4+].C(Cl)Cl>C(O)C.C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:3]=1
Reactant: CCOC(=O)Nc1cc(-c2cccs2)c([N+](=O)[O-])c(N)n1
Agent: [Pd]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)Nc1cc(-c2cccs2)c(N)c(N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
2-Amino-3-nitro-4-(2-thienyl)-6-ethoxycarbonylaminopyridine (1.57 g, 5.1 mmol) and 10% palladium-carbon (255 mg) were dissolved in ethanol (77 ml)-ethyl acetate (38 ml). To this mixture, a 1 M aqueous sodium borohydride solution (15.3 ml) was added at 0° C. and stirred at 0° C. for 1 hour. This solution was mixed with a 5% aqueous ammonium chloride solution (23.4 ml) and filtered through celite. The celite was washed with water (204 ml). The filtrate and this washing solution were mixed and evaporated under reduced pressure to remove ethanol and ethyl acetate, followed by extraction three times with ethyl acetate (150 ml). This solution was dried over sodium sulfate and evaporated under reduced pressure to remove the solvent, followed by silica gel column chromatography (methylene chloride:ethyl acetate=7:3 to 1:1) to purify the desired product, 2,3-diamino-4-(2-thienyl)-6-ethoxycarbonylaminopyridine (Rf 0.39/methylene chloride:ethyl acetate=1:2) (1.28 g, yield 90%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][N:4]=1)#[N:2].[ClH:20].[H][H]>CO.[Pd]>[ClH:20].[NH2:2][CH2:1][C:3]1[N:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:7][N:8]=1
Reactant: [H][H]
Reactant: COC(=O)c1c(F)cccc1-c1cnc(C#N)nc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1c(F)cccc1-c1cnc(CN)nc1
Reaction time: 0.5 h

Procedure:
Methyl 2-(2-cyanopyrimidin-5-yl)-6-fluorobenzoate (100 mg, 0.389 mmol) was dissolved in methanol (4.0 mL) under nitrogen. Palladium on carbon (840 mg, 10% wt/wt) and concentrated HCl (32 μL) were then added prior to exchanging the nitrogen for hydrogen. After 30 minutes the reaction was judged complete (LCMS). The reaction mixture was filtered through celite and the celite was washed with additional methanol. Removal of the solvent under reduced pressure provided methyl 2-[2-(aminomethyl)pyrimidin-5-yl]-6-fluorobenzoate hydrochloride (104 mg) of 90% pure material, as determined by proton NMR and LCMS.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=[C:2]1[NH2:12].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16]N>CO>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:12][C:2]1[CH2:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COC(CN)OC
Reactant: NC1=NC=Cc2ccccc2C1
Solvent: CO
Product: COC(CNC1=NC=Cc2ccccc2C1)OC
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A mixture of 3.16 g of 1H-3-benzazepin-2-amine, 4.17 g of 2,2-dimethoxyethanamine and 50 ml of methanol was stirred for 16 hours at reflux temperature. The reaction mixture was evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was stirred in hexane. The precipitate was filtered off, yielding 4.9 g (100% ) of N-(2,2-dimethoxyethyl)-1H-3-benzazepin-2-amine (interm. 28).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:35])[C@H:17]([NH:31][C:32](=[O:34])[CH3:33])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:32]([NH:31][C@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:35])(=[O:34])[CH3:33]
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 91.5 %

Procedure:
1-(2-(R)-Acetylamino-3-biphenyl-4yl-propionyl)-pyrrolidin-2-(S)-carboxylic acid benzyl ester (0.50 g) were dissolved in 30 mL of methanol and hydrogenated for 4 h at room temperature using 0.3 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.37 g (91%) of the title compound as a white solid. (+)-APCI-MS: 381 (MH+).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:9][C:10]([F:14])([F:13])[C:11]#[N:12]>CC(C)([O-])C.[K+]>[C:3]([C:2](=[C:11]([NH2:12])[C:10]([F:14])([F:13])[F:9])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: N#CC(F)(F)F
Reactant: COC(=O)CC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)C(C(C)=O)=C(N)C(F)(F)F
Yield: 66 %

Procedure:
To a 1 liter, four-necked flask equipped with nitrogen inlet, thermometer, and mechanical stirrer was charged 499.74 g (490 ml, 3.84 mol) of methyl acetoacetate and 12.9 g (0.115 mol) of potassium t-butoxide. The resulting mixture was stirred while 391 g (4.04 mol) of trifluoroacetonitrile was added. The reaction mixture was washed with hexane and the resulting solid was dried in vacuo affording 535 g (62%) of the enamine as a yellow solid; mp 63°-65° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:10][C:11]([O:13][CH:14]([O:16][C:17](=[O:33])[CH2:18][CH:19]([CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:15])=[O:12])[CH3:9]>C(Cl)Cl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH2:8]([O:10][C:11]([O:13][CH:14]([O:16][C:17](=[O:33])[CH2:18][CH:19]([CH2:24][NH2:25])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH3:15])=[O:12])[CH3:9]
Reactant: CCOC(=O)OC(C)OC(=O)CC(CNC(=O)OC(C)(C)C)CC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)OC(C)OC(=O)CC(CN)CC(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99 %

Procedure:
Trifluoroacetic acid (6.5 mL) was added to a solution of compound 4 (0.407 g, 1.08 mmol) and CH2Cl2 (2.85 mL) in an ice water bath, and the solution was maintained in the ice water bath for 30 minutes. The solution was warmed to room temperature and stirred for another 4.5 hours. The reaction solution was then concentrated and dried to give 0.50 g of 3-Aminomethyl-5-methyl-hexanoic acid 1-ethyloxycarbonyloxy-ethyl ester TFA salt 5 (Yield: 99%). 1HNMR (CDCl3, 500 MHz) δ 0.87˜0.91 (m, 6H), 1.23˜1.39 (m, 6H), 1.51 (6rs, 3H), 1.61 (S, 1H), 2.20˜2.38 (m, 1H), 2.40˜2.61 (m, 2H), 2.98˜3.21 (m, 2H), 4.2 (br s, 2H), 6.75 (br s 1H), 7.51˜7.80 (br s, 2H), 9.35˜9.80 (br s, 1H); 13C NMR (CDCl3, 125 MHz) δ13.86, 13.87, 19.16, 19.19, 21.70, 21.74, 22.38, 22.40, 24.83, 30.95, 31.02, 36.48, 36.69, 41.07, 41.32, 44.25, 44.36, 64.82, 91.41, 91.45, 153.38, 153.40, 171.87, 172.08.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:24].[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:11]([C:12]([NH2:13])=[O:24])=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(N)=O
Temperature: 80 °C

Procedure:
480 mg (1.642 mmol) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinonitrile were treated with 3.8 ml sulfuric acid (90%) and heated at 80° C. for 1 hour. The mixture was cooled down to 20-25° C. and treated with 20 ml ethyl acetate. 2.0 g sodium hydroxide solution (28%) was added and the organic phase was washed with 6 ml water. Evaporation in vacuo gave 380 mg of 6-(4-methylpiperazin-1-yl)-4-o-tolyl-nicotinamide as a light yellow crystalline foam.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:23]1[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=1.O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([C:23]2[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:9][CH:8]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1ccc(-c2ccccc2)cc1
Yield: 65.5 %

Procedure:
A mixture of 2M aqueous sodium carbonate solution (6.64 ml), tetrakis(triphenylphosphine)palladium(0) (0.512 g), biphenyl-4-ylboronic acid (2.28 g) and 3-bromopyridin-2-amine (1.532 g) in dehydrated THF (30 mL) was heated under reflux overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. The obtained solid was crystallized from toluene, diisopropyl ether and acetonitrile to give the title compound (1.428 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C@@H:22]1([NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[NH2:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[NH2:28][C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:29][CH:18]1[CH2:19][CH2:20][N:15]([C:2]2([CH3:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@@H]3CCCC[C@H]3N)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 4-methyl-4-(4-oxo-1-piperidyl)piperidine-1-carboxylate (2.0 g, 6.76 mmol) and (1R,2R)-cyclohexane-1,2-diamine (1.55 g, 13.5 mmol) in dichloromethane (60 mL) was added sodium triacetoxyborohydride (2.12 g, 10.0 mmol) and stirred at room temperature for 12 h. Saturated NaHCO3 (40 mL) was added, the phases were separated and the aqueous phase was extracted with dichloromethane (2×60 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[O:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[O:12][C@H:11]1[N:18]1[C:27]2[N:26]=[CH:25][N:24]=[C:22]([NH2:23])[C:21]=2[N:20]=[CH:19]1.C[Si](Cl)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[NH4+]>N1C=CC=CC=1.O>[C:33]([NH:23][C:22]1[C:21]2[N:20]=[CH:19][N:18]([C:27]=2[N:26]=[CH:25][N:24]=1)[C@@H:11]1[O:12][C@H:13]([CH2:16][OH:17])[C@@H:14]([OH:15])[C@H:10]1[O:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[O:2][CH3:1])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CO[C@@H]1CCCC[C@H]1O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CO[C@@H]1CCCC[C@H]1O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 2′-O-(trans-2-methoxy-cyclohexyl)adenosine (0.056 mol) in pyridine (100 mL) is evaporated under reduced pressure to dryness. The residue is redissolved in pyridine (560 mL) and cooled in an ice water bath. Trimethylsilyl chloride (36.4 mL, 0.291 mol) is added and the reaction is stirred at 5° C. for 30 minutes. Benzoyl chloride (33.6 mL, 0.291 mol) is added and the reaction is allowed to warm to 25° C. for 2 hours and then cooled to 5° C. The reaction is diluted with cold water (112 mL) and after stirring for 15 min, concentrated ammonium hydroxide (112 mL). After 30 min, the reaction is concentrated under reduced pressure (below 30° C.) followed by coevaporation with toluene (2×100 mL). The residue is dissolved in ethyl acetate-methanol (400 mL, 9:1) and the undesired silyl by-products are removed by filtration. The filtrate is concentrated under reduced pressure and purified by silica gel flash column chromatography (800 g, chloroform-methanol 9:1). Selected fractions are combined, concentrated under reduced pressure and dried at 25° C./0.2 mmHg for 2 h to give the title compound.