Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH:17]1[CH2:20][N:19]([C:21]([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[CH2:25][CH2:24]2)=[O:22])[CH2:18]1)(=O)=O>CS(C)=O.CCOC(C)=O>[CH:30]1([N:26]2[CH2:27][CH2:28][CH2:29][N:23]([C:21]([N:19]3[CH2:20][CH:17]([O:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:18]3)=[O:22])[CH2:24][CH2:25]2)[CH2:31][CH2:32][CH2:33]1
Reactant: OCc1ccc(F)cc1
Reactant: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(OCc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a stirred solution of (4-fluorophenyl)methanol (27 mg, 0.2 mmol) in DMSO (1.5 mL) was added NaH (8.5 mg, 0.2 mmol, 60% purity) at RT. The mixture was stirred for 1 h and a solution of 1 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl methanesulfonate (33 mg, 0.1 mmol) in DMSO (0.5 mL) was added. The resulting mixture was stirred at 100° C. overnight, cooled to RT and diluted with EtOAc. The crude mixture and washed with water/brine; 1/1 solution, dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by preparative HPLC provided the title compound as colourless oil (8 mg, 18%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].C(N(C(C)C)CC)(C)C.O1CCCC1.Cl.Cl.N1CC[CH:32]([N:35]2[C:43]3[C:38](=[N:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:44])[CH2:31]C1>C(#N)C>[N:8]1([C:1]([N:3]2[CH2:4][CH2:31][CH:32]([N:35]3[C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]3=[O:44])[CH2:6][CH2:7]2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCC(n2c(=O)[nH]c3ncccc32)CC1)n1ccnc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a round bottom flask was added, 1,1′-carbonyldiimidazole (8.59 g, 51.4 mmol), diisopropylethylamine (12.6 mL, 72.2 mmol) and tetrahydrofuran (100 mL). This mixture was warmed to 40° C. and aged for 10 min, after which 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (10 g, 34.3 mmol) was added. The slurry was aged at 40° C. for 3 h, and then upon reaction completion, the solvent was swapped to acetonitrile which afforded an off white solid (9.19 g, 85.9%). LCMS: [M+H]=313; 1H NMR (400 MHz, d6-DMSO) δ 11.58 (1H, s), 8.09 (1H, s), 7.97 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=4.0 Hz), 7.53 (1H, s), 7.05 (1H, s), 7.00 (1H, dd, J=4.0, 8.0 Hz), 4.52, (1H, dd, J=8.0, 12.0 Hz), 4.05 (2H, bd, J=8.0 Hz), 3.31 (2H, m), 2.34 (2H, m), 1.82 (2H, bd, J=12.0 Hz); 13C NMR (100 MHz, d6-DMSO) δ 153.0, 150.4, 143.4, 139.8, 137.2, 128.9, 123.0, 118.7, 116.4, 115.2, 49.3, 45.1, 28.5; mp 226° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:40][N:41]([CH3:51])[C:42]1[CH:47]=[CH:46][C:45]([N:48]=[C:49]=[O:50])=[CH:44][CH:43]=1>>[CH3:40][N:41]([CH3:51])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:4]3[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]4[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=4[O:17][CH3:18])=[CH:6][N:5]=3)[CH2:25][CH2:24]2)=[O:50])=[CH:44][CH:43]=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)Nc3ccc(N(C)C)cc3)CC2)nc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of the compound of Example 59 in the form of its trifluoroacetic acid salt (45 mg), triethylamine (150 μL, 1.08 mmol) was added followed by 4-dimethylamino-phenyl-isocyanate (Aldrich, 33 mg, 0.20 mmol), and the solution was stirred at room temperature for 1.5 hours. The solution was then concentrated and the residue was purified by reverse phase HPLC to give a solid, (34 mg). MS(ES) (M+H)+=508.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH2:9][CH2:10][N:11]1[C:15](Br)=[CH:14][CH:13]=[N:12]1)([CH3:4])([CH3:3])[CH3:2].C[C:28]([N:30](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].[C-]#N.[C-]#N.[Zn+2].[Zn]>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH2:9][CH2:10][N:11]1[C:15]([C:28]#[N:30])=[CH:14][CH:13]=[N:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CC1CCN(C(=O)C(CCn2nccc2Br)NC(=O)OC(C)(C)C)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC1CCN(C(=O)C(CCn2nccc2C#N)NC(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of 0.34 g (0.79 mmol) of [3-(5-bromo-pyrazol-1-yl)-1-(4-methyl-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester (prepared in the synthesis of I-080), 31 mg (0.034 mmol) of Pd2(dba)3, 38 mg (0.069 mmol) of dppf, 96 mg (0.83 mmol) of Zn(CN)2, and 13 mg (0.20 mmol) of Zn powder in 2 mL of DMA is heated to 120° C. for 3 h in a pressure tube. The mixture is cooled, filtered, and purified directly on preparative HPLC to provide 0.22 g (74%) of [3-(5-cyano-pyrazol-1-yl)-1-(4-methyl-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester. This material is then stirred in 2.5 mL of 4 M HCl in 1,4-dioxane for 1 h, and then concentrated to provide I-091.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32]C)=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[Cl:39]C1C=CC=C(F)C=1CC(=O)C(OC)=O.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH3:32])=[O:30])=[CH:21]\[C:22]2[C:23]([F:28])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:39])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)C(=O)Cc1c(F)cccc1Cl
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: COC(=O)/C(=C/c1c(F)cccc1Cl)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 8 %

Procedure:
The title compound was prepared as described for C4 using methyl 3-(2-chloro-6-fluorophenyl)-2-oxopropanoate B16 (100 mg, 0.434 mmol), sodium hydride (10.41 mg, 0.434 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucose bromide (178 mg, 0.434 mmol). The compound was isolated in the form of white solid in 8% yield.
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1([NH:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:19][C:18]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]2[C:3]([N:8]=1)=[N:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1ncccc1Cl
Product: Cc1nc2ncccc2n1-c1ccccc1
Yield: 43.2 %

Procedure:
Method A applied to 3-chloro-2-nitropyridine (79 mg) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as brown viscous oil (45 mg, 43% yield). 1H NMR (DMSO) δ 2.54 (s, 3H), 7.35-7.68 (m, 6H), 7.77 (d, J=8.8Hz, 1H), 8.58 (br s, 1H); 13C NMR δ 14.0, 118.9, 120.1, 126.8, 128.5, 129.6, 130.1, 133.9, 143.0, 151.6, 156.7. HRMS (FAB): cal. for C13H12N3 [M+H+]: 210.1031; found: 210.1026.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][CH:29]([OH:33])[CH:30]([OH:32])[CH3:31])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:33][CH:29]([CH:30]([OH:32])[CH3:31])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: CC(O)C(O)COc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12
Agent: [Pd]
Solvent: CO
Product: CC(O)C(O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(2RS,3RS)-(2,3-dihydroxybutan-1-yl)oxy]quinazoline (950 mg) in methanol (21 ml) is added 10% palladium/carbon (109 mg), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 8 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure, and the residue is crystallized from acetone-diethyl ether. The crystals thus obtained are recrystallized from ethanol - diethyl ether to give 4-[(2RS,3RS)-(2,3-dihydroxybutan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (235 mg) as crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12]>CO>[C:11]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:20](=[N:2][OH:3])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=NO)CC1
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
To a stirred suspension of hydroxylamine hydrochloride (0.84 g, 12.0 mmol) in methanol (10 mL) at 0° C. was added solid Na2CO3 (0.64 g, 6.0 mmol). The mixture was stirred for ca. 5 min. N-t-Boc-4-piperidone (1.99 g, 10.0 mmol) was added and the mixture was stirred for ca 2 h. The reaction mixture was concentrated in vacuo to ca. half its original volume, then diluted with saturated NaHCO3 (100 mL) and extracted with CHCl3 (4×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to yield 1.86 g (87%) of the desired product as a tan solid. MS (ES+) m/z 215.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:23]([C@@H:30]1[CH2:34][O:33][C:32](=[O:35])[N:31]1[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (600 mg, 1.7 mmol), (R)-4-benzyl-oxazolidin-2-one (592 mg, 3.34 mmol), copper(I) iodide (96 mg, 0.5 mmol), N,N-dimethylglycine hydrochloride (140 mg, 1.0 mmol) and potassium carbonate (923 mg, 6.7 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (609 mg, 80%) as a white solid: LC/MS m/e calcd for C28H28N2O4 (M+H)+: 457.55, observed: 457.1.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Brc1ncccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1)c1ncccn1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromopyrimidine
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[OH:20][C:21]1([CH2:31][NH2:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[OH:20][C:21]1([CH2:31][NH:32][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1(O)CCCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(O)CCCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Yield: 86.8 %

Procedure:
A reaction mixture of 1.7 g of 6-chloropurine riboside, 1.7 g of (1,2,3,4-tetrahydro-1-hydroxynaphthyl)methyamine as prepared in Example B hereinafter and 2.0 g of triethylamine is refluxed in 150 ml ethanol for 24 hours. Volatiles are evaporated to dryness and residue is treated with 150 ml of cold water. Clear aqueous solution is decanted off. The water treatment is repeated twice followed by dissolving the residue in methanol and evaporating it to dryness. Co-evaporation several times with methanol affords solid material. It is dried under reduced pressure yielding 2.2 g (85%) of N6 -[1,2,3,4-tetrahydro-1-hydroxy-1-naphthalenyl]methyl adenosine having a melting point of 110°-115° C. Anals. calcd. for C21H25N5O5.0.5 C2H5OH, Found: C=58.65; H=6.26, N=15.55, C=59.27; H=6.34; N=15.53.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:14]=3)[CH2:10][C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1.[O:28]1[CH2:32][CH2:31][CH:30]([CH2:33]C=O)[CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>CN(C=O)C>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:11]3[CH2:12][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:33][CH:30]5[CH2:31][CH2:32][O:28][CH2:29]5)[CH:3]=4)[C:9](=[O:27])[CH2:10]3)[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(C2CC(=O)N(c3cccc(N)c3)C2)cc1OC1CCCC1
Reactant: O=CCC1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(C2CC(=O)N(c3cccc(NCC4CCOC4)c3)C2)cc1OC1CCCC1
Reaction time: 20 h
Yield: 57.7 %

Procedure:
A mixture of 1-(3-aminophenyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one (8 mg, 0.02 mmol), (tetrahydrofuran-3-yl)-acetaldehyde (0.024 mmol), NaB(OAc)3H (0.2 mmol), and AcOH (0.06 mmol) in DMF (0.5 mL) was stirred for 20 h. After concentration under reduced pressure, the residue was dissolved in EtOAc (3 mL), washed with brine (2×3 mL), and dried over Na2SO4. Concentration and chromatography on silica gel (EtOAc:Hexane=1:1) gave 5.2 mg of the desired product. Yield: 57%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([N:15]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]3C=CC=CC=3)=[O:24])=[CH:18][C:17]=2[F:33])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[C:52](OC[C@@H]1OC1)(=[O:56])CCC>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]([N:15]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][C@H:26]([CH2:52][OH:56])[O:25][C:23]3=[O:24])=[CH:18][C:17]=2[F:33])[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(N(C(=O)OCc2ccccc2)C2CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(N(C(=O)OCc2ccccc2)c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.916 g of 3-(benzyloxycarbonyl-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-amino]-azetidine-1-carboxylic acid benzyl ester (1.56 mmol) in 5 ml THF were added at −15° C. 0.767 ml of a 2.25M LDA (1.7 mmol) solution in THF. The mixture was allowed to warm up to 0° C. and stirred for 5 min. Then, 0.26 ml of (R)-glycidyl butyrate (1.87 mmol) was added and the yellow solution was stirred for 2 h at RT. The reaction was quenched with a saturated solution of ammonium chloride. The mixture was diluted with ethyl acetate, the org. layer washed with water and brine and dried over Mg sulfate. The residue was purified by chromatography using a 95/5 dichloromethane/methanol mixture as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][SH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.N[C@H](C(O)=O)CS.C(OC(OC(C)(C)C)=O)(=O)OC(C)(C)C.C(=O)(O)[O-].[Na+].[N+:53]([CH:56]=[CH:57][C:58]1[CH:62]=[CH:61][S:60][CH:59]=1)([O-:55])=[O:54]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][S:11][CH:57]([C:58]1[CH:62]=[CH:61][S:60][CH:59]=1)[CH2:56][N+:53]([O-:55])=[O:54])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CS)C(=O)O
Reactant: O=[N+]([O-])C=Cc1ccsc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N[C@@H](CS)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CSC(C[N+](=O)[O-])c1ccsc1)C(=O)O

Procedure:
N-t-butoxycarbonyl-L-cysteine [prepared from 58.6 g of L-cysteine p-toluenesulfonate, 50 g of di-t-butyl pyrocarbonate and 50 g of sodium bicarbonate in the manner described in Example 63(a)] was treated with 32 g of 1-nitro-2-(3-thienyl)ethylene and 6 g of sodium bicarbonate to give 74.8 g of the title compound as a syrup.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH2:16][CH2:17][NH:18][CH:19]2[CH2:21][CH2:20]2)=[CH:13][CH:12]=1.[H-].[Na+]>>[CH3:2][O:10][CH2:11][CH2:12][CH2:13][N:18]([CH2:17][CH2:16][O:15][C:14]1[CH:22]=[CH:23][C:11]([O:10][C:2]2[S:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)=[CH:12][CH:13]=1)[CH:19]1[CH2:21][CH2:20]1
Reactant: c1cnc2nc(Oc3ccc(OCCNC4CC4)cc3)sc2c1
Agent: [H-]
Agent: [Na+]
Product: COCCCN(CCOc1ccc(Oc2nc3ncccc3s2)cc1)C1CC1

Procedure:
The title compound was prepared from N-{2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenoxy]ethyl}cyclopropanamine using methods analogous to those described for Example 271, using more sodium hydride (2.5 equiv.) and more of the appropriate amine (2 equiv.). 1H NMR (500 MHz, CDCl3): 8.58 (dd, J=4.8, 1.6, 1H), 8.01 (dd, J=7.9, 1.7, 1H), 7.35-7.30 (m, 2H), 7.21 (dd, J=7.9, 4.8, 1H), 6.98-6.93 (m, 2H), 4.13 (t, J=6.2, 2H), 3.43 (t, J=6.4, 2H), 3.35 (s, 3H), 3.05 (t, J=6.2, 2H), 2.82-2.77 (m, 2H), 1.92-1.80 (m, 3H), 0.55-0.42 (m, 4H). MS (ESI): mass calcd. for C21H25N3O3S, 399.16; m/z found, 400.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][C:13]([O:15]CC)=[O:14])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN(C(=O)Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
A solution of ethyl N-(4-chloro-phenylacetyl)-N-phenylglycinate (0.4 g) and 5M NaOH (2.4 ml) in EtOH (12 ml) was refluxed for 2 h. After cooling to rt the mixture was poured into water (30 ml), acidified to pH 2 with 10% HCl and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried over MgSO4, and evaporated. The crude was purified by flash chromatography on silica gel (hexane/ethyl acetate 3:2+3% formic acid) to afford N-((4-chlorophenylacetyl)-N-phenylglycine (0.1 g) as colourless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[N:4][NH:5][C:6]=1[CH3:7].[H-].[Na+].I[CH2:17][CH3:18].[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:17][CH3:18])[C:6]=1[CH3:7]
Reactant: CCI
Reactant: Cc1[nH]nc(-c2ccc(Cl)s2)c1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(Cl)s2)c(Br)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
4-Bromo-3-(5-chloro-2-thienyl)-5-methyl-1H-pyrazole (36.0 mmol) was dissolved in 30 mL dry N,N-dimethylformamide and cooled to 0° C. under nitrogen atmosphere. Sodium hydride (37.8 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. After stirring for 30 min, iodoethane (43.2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was poured into saturated aqueous ammonium chloride solution and extracted with diethyl ether, dried over MgSO4, filtered and evaporated. The crude product was purified by chromatography on silica gel (100% dichloromethane) to afford 7.0 g 4-bromo-3-(5-chloro-2-thienyl)-1-ethyl-5-methyl-1H-pyrazole (64% yield)
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([OH:8])[CH2:4][O:3]1.[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([OH:8])[CH2:4][O:3]1.[CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([O:10][N:11]2[C:12](=[O:21])[C:13]3[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:16])[CH2:4][O:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC1(C)OCC(O)CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(ON2C(=O)c3ccccc3C2=O)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,2-Dimethyl-[1,3]dioxan-5-ol was prepared as described previously (Forbes, D. C. et al.; Synthesis, 1998;6:879-882). 1H NMR (400 MHz; DMSO-d6) δ 4.91 (d, 1 H, J=5.1), 3.70-3.75 (m, 2 H), 3.41-3.46 (m, 3 H), 1.30 (s, 3 H), 1.24 (s, 3 H); MS (APCI+)=132.9. To a stirring solution of 2,2-dimethyl-[1,3]dioxan-5-ol (1.50 g, 11.35 mmol), N-hydroxyphthalimide (1.85 g, 11.35 mmol), and triphenylphosphine (2.98 g, 11.35 mmol) in anhydrous tetrahydrofuran (30 mL) at 0° C. was added diethyl azodicarboxylate (2.3 mL, 14.75 mmol). The resultant solution was allowed to warm to room temperature. After stirring for 3 hours, the mixture was concentrated in vacuo and charged with chloroform affording white solids. The solids were filtered off and filtrate was collected and concentrated. The residue was purified via silica column chromatography (4:1 hexanes/ethyl acetate) affording 2-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-isoindole-1,3-dione as clear crystals (1.74 g, 55% over 2 steps): 1H NMR (400 MHz; DMSO-d6) δ 7.83 (s, 4H), 4.11-4.12 (m, 1H), 4.04-4.09 (m, 2H), 3.92-3.96 (m, 2H), 1.32 (s, 3H), 1.25 (s, 3H); MS (APCI+)=278.0.