Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([NH:8]C(=O)OC(C)(C)C)[CH2:3]1.FC(F)(F)S(O[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[S:39][CH:40]=[CH:41][N:42]=4)[N:33]=3)[CH:30]=2)[N:25]=[CH:24][CH:23]=1)(=O)=O.CCN(C(C)C)C(C)C>CC(O)C>[CH3:1][C@H:2]1[CH2:7][N:6]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]5[S:39][CH:40]=[CH:41][N:42]=5)[N:33]=4)[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:5][C@@H:4]([NH2:8])[CH2:3]1
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(Oc1ccnc2ccc(-c3cccc(-c4nccs4)n3)cc12)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@@H]1C[C@H](N)CN(c2ccnc3ccc(-c4cccc(-c5nccs5)n4)cc23)C1
Yield: 51 %

Procedure:
A solution of tert-butyl (3S,5R)-5-methylpiperidin-3-ylcarbamate (1.5 equiv.) and 6-(6-(thiazol-2-yl)pyridin-2-yl)quinolin-4-yl trifluoromethanesulfonate (1.0 equiv.) and DIEA (2.0 equiv.) in i-PrOH was heated in a microwave at 150° C. (5×20 min). Upon cooling the material was purified directly by RP-HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (3S,5R)-5-methyl-1-(6-(6-(thiazol-2-yl)pyridin-2-yl)quinolin-4-yl)piperidin-3-amine (51%). LC/MS=402.0 (M+H), LC=2.16 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][CH:6]([F:18])[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1>ClCCCl>[F:5][CH:6]([F:18])[O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:12][C:13]=1[N+:1]([O-:4])=[O:2]
Reactant: FC(F)Oc1ccc(OC(F)F)cc1
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(OC(F)F)ccc1OC(F)F
Temperature: 5 °C

Procedure:
10 ml of nitric acid (100%) are added dropwise at a temperature of -5° to 0° C. within 5 minutes to a solution of 13.9 g of 1.4-bis(difluoromethoxy)benzene in 33 ml of 1.2-dichloroethane. The reaction mixture is stirred for a further hour at a temperature of 5° C. and allowed to warm to 15° C. within 1/2 hour. The mixture is then poured into icewater. The organic phase is separated, washed with 10% aqueous sodium hydroxide solution, dried over sodium sulfate and evaporated to dreyness, yielding 12.6 g of crude 2.5-bis(difluoromethoxy)-nitrobenzene in form of a yellowish oil.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:53])([CH3:52])[CH2:11][N:12]1[CH:21]=[C:20]([CH:22]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:37]3[CH:42]=[C:41]([C:43](=[O:48])[NH:44][CH:45]4[CH2:47][CH2:46]4)[CH:40]=[C:39]([F:49])[C:38]=3[CH3:50])[CH:18]=2)[C:13]1=[O:51])(C(C)(C)C)(C)C.C(O)C>Cl.O1CCOCC1>[CH:45]1([NH:44][C:43](=[O:48])[C:41]2[CH:42]=[C:37]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:51])[N:12]([CH2:11][C:10]([CH3:53])([CH3:52])[CH2:9][OH:8])[CH:21]=[C:20]4[CH:22]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[CH3:23])[C:38]([CH3:50])=[C:39]([F:49])[CH:40]=2)[CH2:47][CH2:46]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(C(C)N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C(C)N3CCNCC3)c2c1
Yield: 101.6 %

Procedure:
A solution of tert-butyl 4-(1-{2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}ethyl)piperazine-1-carboxylate (Example 38c, 80 mg) in 4 M HCl in dioxane (1 mL) and ethanol (3 mL) was stirred overnight at room temperature before the volatiles were removed in vacuo. The crude material was dissolved in methanol (2 mL) and loaded onto a 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. The product was eluted with 1 N methanolic ammonia (50 mL) and evaporated in vacuo to afford the title product (58 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:31][NH:30][C:29](=[O:32])[C:4]=2[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.[ClH:33].O1CCOCC1>>[ClH:33].[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)[C:4]2[C:29](=[O:32])[NH:30][CH2:31][C:3]=2[C:2]=1[Br:1]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Br)c3c2C(=O)NC3)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(Br)c3c2C(=O)NC3)cn1
Yield: 22.2 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(7-bromo-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (10 mg, 0.020 mmol) in HCl-dioxane (999 μL, 4.00 mmol) was stirred at RT for 2 h. The mixture was concentrated to a residue, diluted with Et2O (3 mL), and sonicated to yield a white precipitate, which was filtered and dried overnight in a lyophilizer to give an HCl salt of the title compound as a white solid (1.8 mg, 21%). [M+H] calc'd for C17H21BrN6O, 406; found, 406.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)(=O)C>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=CC=Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(=CC=Cc2ccccc2)N1

Procedure:
A solution of hydantoin (40 g), freshly distilled cinnamaldehyde (50 g), and fused sodium acetate (80 g) in acetic acid (160 ml) was heated to reflux for 11/2 hours. The solution was poured into cold water (1.5 l) to precipitate the orange product, which was removed by filtration. This product was washed with water until neutral and then with cold ethanol to give 69 g (85% theoretical yield) of virtually pure product. Before use, the product was recrystallised from ethanol to give yellow crystals of 5-cinnamylidenehydantoin, m.p. 268°-270° (decomp.), the infra-red spectrum of which showed the expected main peaks at 1750, 1700, 1640, 1390, 1350, 1020, 970, 895, 825, 750, 690, and 655 cm-1.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:13]2([C:16]#[N:17])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[C:7]1([C:13]2([CH2:16][NH2:17])[CH2:14][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CC1(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC1(c2ccccc2)CC1
Yield: 73.5 %

Procedure:
LiAlH4 (1.8 g, 48 mmol) is added in batches over 5 min to a solution of 1-phenylcyclopropane carbonitrile (6.58 g, 46 mmol) in ether (200 mL) stirred under N2 at 0°. After 1 h the reaction mixture is quenched by a careful dropwise addition of water (1.8 mL), 10% W/V NaOH solution (1.8 mL) and water (5.4 mL). Vigorous gas evolution again occurs. The mixture is vacuum filtered, and the filtrate is extracted with dilute HCl (0.2M, 3×100 mL). The combined extracts are washed with ether (3×100 mL) and made basic with NaOH pellets (3.2 g, 80 mmol). The aqueous layer is extracted with ether (3×100 mL). The combined organic phases are washed with water (2×100 mL), saturated brine (100 mL) and dried (MgSO4). The solvent is removed under reduced pressure to give (1-phenylcyclopropyl)methylamine (4.98 g, 74%) as an orange oil. Nmr δ (CDCl3) 7.1-7.5 (5H, m), 2.77 (2H, S), 1.3 (2H, br s), 0.6-0.95 (4H, m).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(Cl)=[S:13].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]=[C:12]1[SH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCNCc1ccccc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: SC1=NCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
Solutions of 10.9 g (0.067 mol) N-benzylethylenediamine (Example 2) and 7.65 g (0.067 mol) thiophosgene, each dissolved in 50 ml toluene, were added dropwise and concurrently to a stirred mixture of 14.1 g (0.133 mol) sodium carbonate dissolved in 100 ml water and 100 ml toluene which had been chilled to 0° C. After the 20-30 minute addition period the reaction mixture was allowed to warm to ambient temperature and stirring was continued at this temperature for one hour. The reaction mixture was filtered and the insoluble solid, 7.2 g, was recrystallized twice from methanol-ethyl acetate to give 2.25 g (18% yield) of desired product, m.p. 177°-182° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]([OH:17])=[O:16])(=[O:4])=[O:3].C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][S:2]([C:5]2[C:6]3[C:11](=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:4])=[O:3])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)O)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
5-Chlorosulfonyl-naphthalene-1-carboxylic acid 45 (2.00 g, 7.39 mmol) was dissolved in dichloromethane (30 mL). Triethylamine (2.24 g, 3.1 mL, 22.2 imnol) was added followed by 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1,63 g, 8.13 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane (50 mL) and charged to a separatory funnel. The organic layer was washed twice with water and brine and dried over MgSO4. Filtration and concentration in vacuo afforded 46 (3.0 g, 93%) as a yellow foam. 1H NMR (300 MHz, d6-DMSO) δ 9.11 (d, 1H), 8.62 (d, 1H), 8.15 (d, 1H), 7.90 (d, 1H), 7.62 (m, 2H), 3.91 (d, 1H), 3.62 (m, 2H), 3.15 (m, 1H), 2.67 (m, 2H), 1.89 (m, 2H), 1.52 (m, 2H), 1.40 (s, 9H); LC/MS m/z 435 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][C:14]=2[F:20])=[CH:10][C:9](=[O:21])[N:8]([CH3:22])[CH:7]=1)=[O:5])[CH3:2].[C:23]([Si](C)(C)C)#[CH:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CN(C=O)C.[Cu]I.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>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:23]#[CH:24])=[CH:15][C:14]=2[F:20])=[CH:10][C:9](=[O:21])[N:8]([CH3:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)OCC)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (1.0 g, 2.40 mmol) was reacted with ethynyl-trimethyl-silane (0.70 mL, 4.80 mmol) in the presence of CuI (0.23 g, 1.20 mmol), (Ph3P)2PdCl2 (0.085 g, 0.12 mmol) and TEA (10 mL) in THF/DMF (4:1, 25 mL) which was stirred at room temperature for 24 hours. The reaction mixture was filtered pass through a pad of alumina (neutral). The filtrate was partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was dried and concentrated under reduced pressure. The resulting residue was dissolved in THF (10 mL) and treated with the tetrabutylammonium fluoride (1M in THF, 2.40 mL, 2.4 mmol) which was stirred at room temperature for 15 hours. The reaction was partitioned between water (20 mL), and EtOAc (100 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester as a light brown solid (0.67 g, 88%). 1H NMR [(CDCl3, 400 MHz] δ9.56 (s, 1H), 8.22 (s, 1H), 7.38 (dd, J=10.1, 1.9 Hz, 1H), 7.25 (s, 2H), 6.01 (s, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.53 (s, 3H), 3.09 (s, 1H), 1.38 (t, J=7.1 Hz, 3H). Anal. Calcd for C17H15FIN2O3: C, 64.96; H, 4.81; N, 8.91. Found: C, 64.89; H, 4.40; N, 8.64.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].Cl.[Cl:7][CH2:8][C:9]([NH2:11])=[NH:10].C(N(CC)CC)C>CCO>[NH2:4][C:3]1[CH:2]=[CH:5][N:11]=[C:9]([CH2:8][Cl:7])[N:10]=1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccnc(CCl)n1
Reaction time: 1 h

Procedure:
2-Chloroacrylonitrile (35 ml.) was added in portions over 15 minutes to a solution of chloroacetamidine hydrochloride (55 g.) and triethylamine (120 ml.) in EtOH (250 ml.) cooled to 10°. The temperature was allowed to rise to 40° over 1 hour. The mixture was cooled and filtered and the resulting solution evaporated in vacuo. The residue was taken up in EtOAc (600 ml.) from which a tar precipitated. The solution was treated with decolourising carbon, filtered and evaporated to give 4-amino-2-chloromethylpyrimidine as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2cccc(Cl)c2N1
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc([N+](=O)[O-])cc(Cl)c2N1
Temperature: -45 °C
Reaction time: 8 h

Procedure:
7-chloro-1,3-dihydro-2H-indol-2-one (8.0 g, 47.7 mmol) was slurried in H2SO4 (conc., 86 ml) and the mixture cooled to −45° C. A solution of fuming nitric acid (>90%, 3.34 g, 52.9 mmol) in H2SO4 (20 ml) was added drop wise, while maintaining the temperature at −45° C. throughout the addition. The mixture was allowed to slowly warm to RT and stirred overnight. The mixture was poured into stirred ice-cold water (1500 ml). A white precipitate resulted, and the slurry was aged at 0° C. for 1 hour. The solid was collected by filtration, triturated with cold water (2×), and dissolved into EtOAc (1 L). This mixture was filtered, washed with basic brine (containing sodium bicarbonate), dried over Na2SO4, filtered, and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[H][H]>[Pd].C(O)C>[N:5]1([C:1](=[O:4])[CH2:2][CH3:3])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CCC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A Parr shaker bottle was charged with a suspension of benzyl 4-propionylpiperazine-1-carboxylate (16), 10% palladium on carbon, 50% wet (900 mg) and absolute ethanol (100 mL). The Parr bottle was filled with 20 psi of hydrogen and shook for 3 h at rt. The resulting suspension was filtered through Celite and concentrated to yield the title compound (4.31 g, 93%) as a clear, colorless oil: 1H NMR (500 MHz, CDCl3) δ 3.75-3.63 (m, 2H), 3.48-3.42 (m, 2H), 2.87-2.80 (m, 4H), 2.34 (q, J=7.5 Hz, 2H), 1.98 (br s, 1H), 1.15 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][CH2:52][CH2:53][C:54]1([C:59](O)=[O:60])[CH2:58][CH2:57][CH2:56][CH2:55]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:59]([C:54]1([CH2:53][CH2:52][O:51][CH3:50])[CH2:58][CH2:57][CH2:56][CH2:55]1)=[O:60]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: COCCC1(C(=O)O)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3c(C)n(C)c(=O)n(C)c3=O)cc2)C(=O)OC)CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.4 mmol, 173 mg), HBTU (0.5 mmol, 189 mg) and 1-(2-methoxyethyl)cyclopentane carboxylic acid (0.5 mmol, 86 mg) in DMF (2 mL) was added diisopropylethylamine (1.2 mmol, 0.29 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 24 h at room temperature. The resulting dark-brown solution was diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed successively with 1N hydrochloric acid (2×30 mL), saturated sodium bicarbonate solution (30 mL), and brine solution (30 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel column chromatography using a Biotage (40m) column to afford 139 mg (72% yield) of N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. FAB-HRMS m/e calcd for C26H35N3O6 (M+H) 486.2604, found 486.2602.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[CH2:27][CH2:26][N:25]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCNCC4)no2)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CC(=O)OC(C)(C)C)CC4)no2)cc1Cl
Temperature: 100 °C
Yield: 92 %

Procedure:
In a 5 ml microwave reaction vessel was added 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 8) (110 mg, 0.262 mmol). Then potassium carbonate (101 mg) was added followed by 1,1-dimethylethyl bromoacetate (51.0 mg, 0.262 mmol). The reaction mixture was heated at 100° C. for 10 minutes. The cooled reaction mixture was diluted with DCM (5 ml) and purified by SCX (washing with methanol and eluting the crude amino ester with methanolic ammonia). 1,1-dimethylethyl [6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]acetate (120 mg, 0.241 mmol, 92% yield) was isolated as a pale yellow oil. MS (ES) C27H3235ClN3O4 requires 497; found 498 [M+H]+.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][CH:31]=1>>[C:34]([C:33]1[CH:37]=[CH:38][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)(=[O:35])[NH2:36]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: NC(=O)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (326 mg, 0.83 mmol) is coupled to 4-bromobenzamide (200 mg, 0.99 mmol) using Method B to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=1>C(Cl)Cl.CN(C=O)C>[CH3:17][S:18][C:19]1[CH:20]=[CH:21][C:22]([S:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[N:31]([C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH2:30][CH2:29]3)=[CH:23][CH:24]=1
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Reactant: CSc1ccc(Sc2ccc3c(c2)CCN3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1ccc(Sc2ccc3c(c2)CCN3C(=O)[C@@](C)(O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
Oxalyl chloride (0.35 ml, 4.0 mmol) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (0.58 g, 3.7 mmol) (Method A) in DCM (10 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 18 hours and was then added to a solution of 5-(4-methylsulphanylphenylsulphanyl)indoline (1.03 g) (Method B) and 2,6-diphenylyridine (0.84 g, 3.64 mmol) in DCM (20 ml). The mixture was stirred for 16 hours, volatile material was removed by evaporation, and the residue was purified by flash column chromatography on silica gel eluting with 10-20% EtOAc/iso-hexane to give the title compound (0.935 g, 2.3 mmol) as a solid. NMR: 1.80 (s, 3H), 2.50 (s, 3H), 3.11-3.19 (m, 2H), 4.19-4.29 (m, 1H), 4.38-4.47 (m, 1H), 4.86 (s, 1H), 7.19-7.27 (m, 6H), 8.20 (d, 1H); m/z (+ve ESP): 414 (M+H)+.
Reaction SMILES: C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N:19]1C2N=C(N)N=C(N)C=2N=C1)(=O)C.N(OC(C)(C)C)=O.N([O-])=O.[Na+].[C:41]([O:44][C@@H:45]1[C@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@@H:48]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:47][C@H:46]1[N:59]1[C:68]2[N:67]=[C:66]([F:69])[N:65]=[C:63]([NH2:64])[C:62]=2[N:61]=[CH:60]1)(=[O:43])[CH3:42]>COCCOC.N1C=CC=CC=1>[NH3:19].[C:41]([O:44][C@@H:45]1[C@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@@H:48]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:47][C@H:46]1[N:59]1[C:68]2[N:67]=[C:66]([F:69])[N:65]=[C:63]([NH2:64])[C:62]=2[N:61]=[CH:60]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)nc(F)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(C)ON=O
Agent: O=N[O-]
Solvent: c1ccncc1
Solvent: COCCOC
Product: N

Procedure:
It is further known in the literature that 2-aminoadenosine-2',3',5'-tri-O-acetate can be converted with tert-butyl nitrite or sodium nitrite in 50% HF/pyridine to a mixture of the corresponding 2-fluoroadenosine-2',3',5'-tri-O-acetate and 2,6-difluoro-nebularine-2',3',5'-tri-O-acetate, which, with dry ammonia gas in 1,2-dimethoxy-ethane, yields pure 2-fluoroadenosine-2',3',5'-tri-O-acetate in about a 60% yield (M. J. Robins, B. Uznanski, Can. J. Chem. 59, 2608 (1961)). A drawback of this process, however, is that because of the obtained mixture, another reaction step is necessary to obtain the pure 2-fluoronucleoside.