Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[C:15]2[S:16][C:17]3[C:21]4[S:22][C:23](C(O)=O)=[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:20]=4[S:19][C:18]=3[C:14]=2[S:13][C:12]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(=O)=O.CCCCCC>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[CH2:25]([C:24]1[C:20]2[S:19][C:18]3[C:14]4[S:13][CH:12]=[C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:15]=4[S:16][C:17]=3[C:21]=2[S:22][CH:23]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c3sc(C(=O)O)c(CCCCCCCCCC)c3sc21
Agent: [Cu]
Agent: O=C=O
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCCCc1csc2c1sc1c3scc(CCCCCCCCCC)c3sc21
Temperature: 255 °C
Yield: 62.5 %

Procedure:
Compound 75 (13.5 g, 0.021 mol) was mixed with copper powder (0.9 g) in quinoline (80 mL), and the mixture was heated to 250-260° C. in a Woods-metal bath. When no further bubbles of carbon dioxide gas could be detected (about 2 hours), the mixture was allowed to cool to room temperature and hot hexane (400 mL) was added. This mixture was then repeatedly washed by HCl (2N, 4×50 mL). The hexane was partially removed by evaporation, and the resultant solid was collected by filtration and re-crystallized from hexane to afford compound 70 (7.0 g, 60.6% yield). M.p. 111.0-113.3° C. 1H NMR (C6D6) δ 6.53 (s, 2H), 2.51 (t, 4H), 1.64 (m, 4H), 1.27 (m, 28H), 0.89 (t, 6H). 13C NMR: 141.26, 136.42, 133.17, 132.04, 120.73, 32.31, 30.03, 29.96, 29.90, 29.79, 29.66, 29.04, 23.07, 14.28.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24](=[O:39])[C:25]4[C:30]([C:31]=3[CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12.C(O)C>C(Cl)Cl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]([C:22]3[O:23][C:24](=[O:39])[C:25]4[C:30]([C:31]=3[CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3CN3CCOCC3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CC(c1oc(=O)c2ccccc2c1CN1CCOCC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 15.6 %

Procedure:
To a solution of 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(morpholinomethyl)-1H-isochromen-1-one (0.033 g) in dry DCM (2 ml), 1M BBr3 in DCM (0.93 ml, 0.93 mmol) was added and the solution was stirred at room temperature for 2.5 hrs. The solution was cooled to 0° C. and ethanol (8 ml) was added. The solution was evaporate to dryness and crude was purified by flash chromatography in silica-NH cartridge (DCM to DCM:MeOH=90:10) affording title compound as a pale orange solid (5 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:35]2[CH:39]=[CH:38][NH:37][N:36]=2)O1>CN(C=O)C.O1CCOCC1.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>[OH:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:39]=[CH:38][NH:37][N:36]=4)=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[NH:12][C:13](=[O:20])[C:14]=1[C:18]#[N:19]
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: N#Cc1c(O)c2c(-c3ccc(I)cc3)csc2[nH]c1=O
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: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1c(O)c2c(-c3ccc(-c4cc[nH]n4)cc3)csc2[nH]c1=O
Temperature: 130 °C

Procedure:
To a suspension of 3-(4-iodo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (60 mg, 0.15 mmol) and MgO (18 mg, 0.45 mmol) in 2 mL DMF and 2 mL dioxane, was added Cs2CO3 (0.45 mL, 1M solution in H2O), followed by 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (38 mg, 0.2 mmol), and Pd(PPh3)4 (10 mg, 0.008 mmol). The reaction was heated to 130° C. using microwave reactor for 15 min, filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 335 (M+H)+; 1H NMR (500 MHz, DMSO-d6): δ 6.61 (s, 1H), 7.00 (s, 1H), 7.43 (d, J=8.42 Hz, 2H), 7.49 (d, J=8.42 Hz, 2H), 8.04 (s, 1H).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].N1C=CN=C1.[CH3:11][C:12]([CH3:17])([CH2:15][Cl:16])[CH2:13][OH:14]>C1CCCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:14][CH2:13][C:12]([CH3:17])([CH3:11])[CH2:15][Cl:16]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(CO)CCl
Agent: c1c[nH]cn1
Solvent: C1CCCCC1
Product: CC(C)(CCl)CO[Si](C)(C)C

Procedure:
The initiator of structure (3), designated PFI10, was prepared using the procedures broadly described in WO 91 112277. The hydroxyl functionality in 2,2-dimethyl-3-chloropropanol was protected by reaction with trimethylsilyl chloride. A solution of trimethylsilyl chloride (27.16 g, 0.25 mol) in dry cyclohexane (150 g) was treated with 20.4 g of imidazole (0.30 mol) under an argon atmosphere. The resulting slurry was stirred vigorously at room temperature as 2,2-dimethyl-3-chloropropanol (30.93 g, 0.25 mol) was added slowly to the mixture. The rate of addition was controlled to keep the reaction temperature below 40° C. The resulting slurry was filtered affording a clear solution of the desired 1-trimethylsilyloxy-2,2-dimethyl-3-chloropropane. Analysis using a Gas Chromatography-Mass Spectroscopy (GC-MS) technique found essentially no side products. The trimethylsilyl protected adduct was obtained in quantitative yield. A repeat of this experiment gave similar results.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23](C2C=CN=CC=2)[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33]CCl>[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([Cl:33])[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CO)cc2n1C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: [Mn+4]
Agent: [O-2]
Product: COc1nnc(Cl)cc1-c1cc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
2.7 g 6-Hydroxymethyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-car-boxylic acid tert-butyl ester is dissolved in 80 mL dichloromethane. After addition of 3.61 g activated manganese (IV) oxide the reaction mixture is heated to reflux for 1 hour. Then every two hours additional manganese (IV) oxide is added until the conversion is complete. The reaction mixture is diluted with dichloromethane and filtered over celite. 2.68 g (100%) crude product is obtained, which is directly used in the next reaction.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH2:16][O:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=4)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1>>[Br:2][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[N:20]=[C:19]([CH2:18][O:17][CH2:16][C:12]3([C:9]4[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=4)[CH2:15][CH2:14][CH2:13]3)[O:23][N:22]=2)=[CH:25][CH:26]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(-c2noc(COCC3(c4ccc(Cl)cc4)CCC3)n2)cc1
Product: Clc1ccc(C2(COCc3nc(-c4ccc(CBr)cc4)no3)CCC2)cc1
Reaction time: 16 h
Yield: 94.5 %

Procedure:
Phosphorous tribromide (30 μL, 323 μmol) was added to a stirred solution of crude (4-(5-(((1-(4-chlorophenyl)cyclobutyl)methoxy)methyl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (83 mg, 215 μmol) at 0° C. The ice bath was removed and stirring was continued for 16 h. The reaction mixture was diluted with dichloromethane and water. The dichloromethane extract was washed with satd. Aqueous NaHCO3 solution, brine, dried (Na2SO4), filtered, and evaporated under reduced pressure to obtain crude 3-(4-(bromomethyl)phenyl)-5-(((1-(4-chlorophenyl)cyclobutyl)methoxy)methyl)-1,2,4-oxadiazole (91 mg, 95% crude yield). LC/MS: m/e 448.92 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:55][CH:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a solution of 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.50 mmol) and TBTU (177 mg, 0.55 mmol) in DMF (2.5 mL) was added DIPEA (428 μL, 2.50 mmol). Then 4-aminotetrahydropyran (56 mg, 0.55 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 0 to 100% ethyl acetate in heptane, then 5% methanol in dichloromethane) afforded the title compound (43 mg, 22%) as a white solid after recrystallisation from ethyl acetate/heptane. MS: m/e=394.1 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:15])(=O)=O>ClCCl>[Cl:15][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[O:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1cc(OC2CCCC2)cs1
Solvent: ClCCl
Product: Clc1sccc1OC1CCCC1
Reaction time: 1 h
Yield: 57.2 %

Procedure:
2-Chloro-3-cyclopentyloxythiophene was prepared according to the procedures described in P. Stanetty and E. Puschautz, Monatshefte Chemie, 1989, 120, 65. Thus, to a solution of 3-cyclopentyloxythiophene (3.98 g, 23.7 mmol) in dichloromethane (35 mL) was added sulfuryl chloride (2 mL, 24.9 mmol) at 15° C. under argon. The mixture was stirred for 1 hour, then concentrated to dryness. Purification by flash chromatography (silica, 100% hexane) gave 2-chloro-3-cyclopentyloxythiophene (2.75 g, 59%) as a pale yellow oil; 1HNMR 300 MHz, CDCl3) δ 6.99 (d, J=6.0 Hz, 1 H), 6.75 (d,J=6.0 Hz, 1 H), 4.69-4.74 (m, 1H), 1.7-1.93 (m, 6H), 1.5-1.7 (m,2H). MS m/e (%): 202 (M+; 6).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([CH3:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:7][C@@H:6]1[C@@H:2]([O:1][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2C)cc1
Reaction time: 8 h
Yield: 92.8 %

Procedure:
(3R,4S)-benzyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate (19.6 g, 83 mmol) was dissolved in pyridine (83 ml). To the above solution, Ts-Cl (22.2 g, 117 mmol) was added in portions at rt. After overnight stirring, the reaction mixture was concentrated in vacuo to remove pyridine. The residue was quenched with ice water (200 mL), extracted with ethyl acetate (3×150 mL). The combined ethyl acetate phase was washed with water, 1N HCl, water and sat. NaHCO3, then dried with Na2SO4. After concentration, (3S,4R)-benzyl 3-methyl-4-(tosyloxy)pyrrolidine-1-carboxylate (30 g, 92% yield) was obtained as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76-7.83 (2 H, m), 7.30-7.40 (7 H, m), 5.11 (2 H, s), 4.57-4.64 (1 H, m), 3.56-3.73 (2 H, m), 3.38-3.54 (1 H, m), 3.08-3.19 (1 H, m), 2.33-2.55 (4 H, m), 0.97 (3 H, dd, J=14.86, 7.15 Hz); LCMS (Chromolith RP-18e 2.0×50 mm, 0.8 mL/min, Solvent A: 10% MeOH/water with 0.1% TFA, Solvent B: 90% MeOH/water with 0.1% TFA, gradient with 0-100% B over 4 minutes) retention time: 3.60 min; MS (ES+) m/z: 390 (M+H+);
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[C:11](Cl)(=O)[C:12](Cl)=[O:13].C(N(CC)CC)C.[Cl:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH2:35][C:36]([OH:38])=[O:37])[CH:32]=[CH:33][CH:34]=1>C(OCC)C.ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:13])[O:37][C:36](=[O:38])[C:35]=2[C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:27][CH2:26][CH2:25][Cl:24])[CH:30]=2)=[CH:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(OCCCCl)c1
Reactant: Cn1ccc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cccc(OCCCCl)c3)C(=O)OC2=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-methylindole (1.16 mL, 9.1 mmol) in diethyl ether (70 mL) at 0° C. was added dropwise oxalyl chloride (0.83 mL, 1.1 eq.). After the additon, the reaction mixture was stirred at 0° C. for 15 min., and the volatiles were removed under vacuo. The residue was re-dissolved in dichloromethane (70 mL) and triethylamine (2.3 mL, 2 eq.) was added. The reaction mixture was cooled to 0° C. and a solution of 3-(3-chloro-propyloxy)phenylacetic acid (2.73 g, 10 mmol) in dichloromethane (70 mL) was added dropwise. The resulting mixture was stirred at 0° C., and then allowed to warm up to room temperature overnight. Volatiles were removed under vacuo and the residue was purified on a silica gel column with dichloromethane to give 3-(1-methylindol-3-yl)-4-[3-(3-chloropropyloxy)phenyl]furan-2,5-dione (1.1 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH2:10][CH3:11])(=[O:7])[OH:6].C(=O)(O)[O-].[Na+].[C:17]([O:22][CH:23]([O:25][C:26](OC1CC(=O)NC1=O)=[O:27])[CH3:24])(=[O:21])[CH:18]([CH3:20])[CH3:19]>O.C(#N)C.C(OC(=O)C)C>[C:17]([O:22][CH:23]([O:25][C:26]([NH:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])[OH:7])=[O:27])[CH3:24])(=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: CCCCP(=O)(O)CCCN
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCP(=O)(O)CCCNC(=O)OC(C)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-aminopropyl(n-butyl)phosphinic acid (10 mmol) and sodium bicarbonate (20 mmol) in water (40 mL) was added a solution of compound (17) (10 mmol) in acetonitrile (20 mL) over 1 min. The reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with ethylacetate (100 mL) and washed with 0.1 M aqueous potassium bisulfate (3×100 μL). The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (31) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 6.78 (q, J=8 Hz, 1H), 3.49 (s, 1H), 3.28 (t, J=6.4 Hz, 2H), 2.51-2.55 (m, 1H), 1.80-1.84 (m, 2H), 1.65-1.75 (m, 3H), 1.55-1.58 (m, 2H), 1.39-1.48 (m, 4H), 1.17 (d, J=8.4 Hz, 9H), 0.93 (t, J=7.2 Hz, 3H). Phosphorus (162 MHz, CDCl3) δ0.31. MS (ESI) m/z 338 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=O)(=[O:25])=[O:24])[CH:17]=[CH:16]2.[N:32]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1=[O:38].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23]([CH2:26][C@@H:27]([OH:31])[C:28]([N:42]1[CH2:41][CH2:40][CH:39]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]3=[O:38])[CH2:44][CH2:43]1)=[O:30])(=[O:24])=[O:25])[CH:17]=[CH:16]2
Reactant: O=C1CCCCN1C1CCNCC1
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCC(N2CCCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 54 %

Procedure:
WSC (0.19 g) was added to a mixture of (2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropionic acid (0.31 g), 1,4′-bipiperidin-2-one (JP 2001-524466 A) (0.18 g) and HOBt (0.15 g) in DMF (15 mL) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and diluted with dichloromethane and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1) to obtain the title compound (0.26 g, 54%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:9](=[O:10])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Cc1ccccc1CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 53.6 %

Procedure:
To a stirred solution of 0.334 g of 2-methylphenylacetyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered through a pad of hydrous magnesium silicate and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl acetate to give 0.385 g of the desired product as white crystals, m.p. 198-200° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([NH:18][CH2:19][CH:20]=[CH2:21])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])C.C([CH:24]([C:28](Cl)=[O:29])[C:25](Cl)=[O:26])C.O.Cl.[CH2:33]([O:35]CC)[CH3:34]>C(O)C>[CH2:33]([O:35][C:28]([C:24]1[C:25](=[O:26])[N:18]([CH2:19][CH:20]=[CH2:21])[C:7]2[N:8]=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=[CH:11][C:6]=2[C:4]=1[OH:5])=[O:29])[CH3:34]
Reactant: C=CCNc1nc(-c2ccccc2)ncc1C(=O)OCC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CCOCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: C=CCn1c(=O)c(C(=O)OCC)c(O)c2cnc(-c3ccccc3)nc21

Procedure:
To 16.3 g. (0.057 mole) of 4-(2-propenylamino)-2-phenyl-5-pyrimidine carboxylic acid ethyl ester in diethyl ether was added 4.3 g. (0.029 mole) of ethyl malonyl chloride and then stirred 3 hours at room temperature. The reaction was then filtered and stripped to dryness and the residue was added to a solution of 1.3 g. (0.057 mole) of Na in ethanol and stirred at room temperature for 10 minutes. Water was added until the reaction became clear and then acidified with HCl. This solution was chilled in ice and the resulting solid was removed by filtration. Recrystallization from ethyl acetate gave 0.55 g. of title product with m.p. 174°-175° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:28])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH2:19])[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:28])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH:19][C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=1)[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1
Reactant: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@@H](N)Cc2cccc(C)c2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)Nc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-L-phenylalaninamide (0.6 g, 1.42 mmol) in CH2Cl2 (15 mL) is added 4-fluorophenylboronic acid (0.398 g, 2.85 mmol), cupric acetate (0.26 g, 1.4 mmol) and pyridine (0.23 mL, 2.85 mmol), and the dark blue solution is stirred overnight at room temp. The solution is then diluted with CH2Cl2 (35 mL), and washed with 1 N HCl (50 mL) and brine (50 mL), then dried (MgSO4), evaporated and chromatographed (silica, 30% EtOAc/hexane) to yield N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-(4-fluorophenyl)-L-phenylalaninamide, as a clear oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)[CH:7]=1)=[O:4].[NH:28]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[N:29]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O1CCOCC1.ClCCCl>[NH:28]1[CH:32]=[CH:31][C:30]([CH2:33][NH:1][C@@H:2]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:3]([NH:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=3)[CH:7]=2)=[O:4])=[N:29]1
Reactant: CNc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)ccn1
Reactant: O=Cc1cc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCc3cc[nH]n3)n(C)n2)ccn1
Reaction time: 1 h
Yield: 28.1 %

Procedure:
To (2S)-2-amino-3-(4-fluorophenyl)-N-(1-methyl-3-(2-(methylamino)pyridin-4-yl)-1H-pyrazol-5-yl)propanamide (79 mg, 214 μmol) was added 1H-pyrazole-3-carbaldehyde (29 mg, 300 μmol), then DCE and dioxane were added as solvents, followed by acetic acid (13 μl, 225 μmol) and NaBH(OAc)3 (136 mg, 643 μmol). Heating was continued for 1 hr. 40 min. The reaction was concentrated and purified by reverse phase HPLC purification to afford 23.2 (27 mg, 28%) as a white solid. 1H NMR (400 MHz, MeOH) δ ppm 7.77-8.01 (m, 1H) 7.55 (br. s., 1H) 7.25 (dd, J=8.61, 5.48 Hz, 2H) 7.03 (t, J=8.80 Hz, 2H) 6.91 (dd, J=5.67, 1.37 Hz, 1H) 6.51-6.65 (m, 1H) 6.23 (d, J=1.96 Hz, 1H) 3.74-3.91 (m, 2H) 3.60-3.63 (m, 1H) 3.59 (s, 3H) 2.97-3.11 (m, 2H) 2.89 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CN(C1CCOCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C1CCNCC1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of 4-[methyl(tetrahydropyran-4-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (101 mg, 0.34 mmol) and TFA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording Methylpiperidin-4-yl(tetrahydropyran-4-yl)amine as a white solid (66 mg, 97%). 1H NMR (CDCl3, 300 MHz): δ 4.05-3.97 (m, 2H); 3.38 (td, J=10.9, 3.8 Hz, 2H); 3.19 (d, J=12.1 Hz, 2H); 2.84-2.57 (m, 5H); 2.27 (s, 3H); 1.80-1.49 (m, 8H).