Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(=O)CCCCC1.[C:16](#[N:18])[CH3:17]>O>[C:5]1(=[CH:17][C:16]#[N:18])[CH2:4][CH2:3][CH2:8][CH2:7][CH2:6]1
Reactant: CC#N
Reactant: CCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=C1CCCCC1
Product: N#CC=C1CCCCC1
Temperature: 55 °C

Procedure:
A 10 l round-bottom flask is loaded with 285 g (4.57 mols) of 90% potassium hydroxide in flakes and 1775 ml of hexane. The mixture is heated to 55° C. and, keeping heating, a solution consisting of 450 g (4.59 mols) of cyclohexanone and 1351 ml of acetonitrile is quickly dropped therein (during the addition temperature falls to 52.6° C.). The mixture is refluxed for 7 hours, then cooled at room temperature. 2863 ml of water are added thereof to dissolve the solid. The organic phase is washed twice with water (1000 ml each). The phases are separated and the organic phase is evaporated to dryness under vacuum, to obtain 462 g of a residue which is distilled under 10 mmHg at 100-105° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27]I)=[CH:21][C:20]=2[F:29])=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][O:8][CH2:9][CH2:10][O:11]C=C)=[O:6].[CH3:30][NH:31][CH3:32].Cl.C([O-])([O-])=O.[K+].[K+].[Na+].[Cl-]>CC(N(C)C)=O.O.CCO>[CH3:30][N:31]([CH3:32])[CH2:27][CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:3]2[C:2]([F:1])=[C:16]([F:17])[CH:15]=[CH:14][C:4]=2[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6])=[C:20]([F:29])[CH:21]=1
Reactant: CNC
Reactant: C=COCCONC(=O)c1ccc(F)c(F)c1Nc1ccc(CCCI)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)CCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 36 %

Procedure:
3,4-Difluoro-2-[2-fluoro-4-(3-iodopropyl)anilino]-N-[2-(vinyloxy)ethoxy]benzamide (200 mg, 0.39 mmol) was dissolved in DMA (10 mL), to which was added dimethylamine (0.15 mL of a 40% solution in water). This mixture was stirred at RT for 15 hours, then the DMA removed under reduced pressure, affording a yellow oil. This oil was then dissolved in EtOH (6 mL), to which was added 1 M HCl solution (4 mL). The resulting mixture was stirred at RT for 15 h. The reaction mixture was then diluted with water (50 mL) and this aqueous solution basicified with solid K2CO3 and saturated with solid NaCl. The resulting solution was extracted with EtOAc (3×50 mL), the combined organic extract dried (Na2SO4) and the solvent removed under reduced pressure to afford an oil. This oil was purified by column chromatography on silica gel (1% NH4OH in 25% MeOH/CH2Cl2 as eluant) to give 2-{4-[3-(dimethylamino)propyl]-2-fluoroanilino}-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a cream foam (55 mg, 36%). 1H NMR [400 MHz, (CD3)2SO] δ 11.70 (v br s, 1 H), 8.82 (br s, 1 H), 7.44-7.38 (m, 1 H), 7.14-7.06 (m, 1 H), 7.05 (dd, J=12.5, 1.6 Hz, 1 H), 6.89 (dd, J=8.2, 1.6 Hz, 1 H), 6.82 (ddd, J=8.7, 8.7, 4.5 Hz, 1 H), 4.53 (br s, 1 H), 3.85 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 2 H), 2.53 (t, J=7.5 Hz, 2 H), 2.24 (t, J=7.1 Hz, 2 H), 2.16 (s, 6 H), 1.67 (q, J=7.5 Hz, 2 H). Anal. calcd. for C20H24F3N3O3.0.75H2O: C, 56.5; H, 6.1; N, 9.9. Found C, 56.4; H, 6.4; N, 9.1.
Reaction SMILES: N1C2C(=CC=CC=2)C(C2CCC(=O)CC2)=C1.O1[C:21]2([CH2:26][CH2:25][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([C:36]#[N:37])[CH:34]=4)[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[O:20]CC1>>[C:36]([C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:24]1[CH2:25][CH2:26][C:21](=[O:20])[CH2:22][CH2:23]1)#[N:37]
Reactant: N#Cc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Agent: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: N#Cc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Yield: 79.6 %

Procedure:
This compound was prepared in the manner described above for intermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1H-indole (6 g) to afford 4.03 g (81%) of the title compound as a white solid: mp 162.5-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.O.[OH:52]N1C2C=CC=CC=2N=N1.[Cl:62][C:63]1[C:70]([Cl:71])=[CH:69][CH:68]=[CH:67][C:64]=1[CH2:65][NH2:66].CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:10][N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3].[Cl:62][C:63]1[C:70]([Cl:71])=[CH:69][CH:68]=[CH:67][C:64]=1[C:65]([NH2:66])=[O:52]
Reactant: NCc1cccc(Cl)c1Cl
Reactant: On1nnc2ccccc21
Agent: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)CN1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[2(R)-(t-butoxycarbonyl)amino-3-triphenylmethylmercaptopropyl]-L-proline (0.08 g, 0.153 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.035 g, 0.184 mmol), and 1-hydroxybenzotriazole hydrate (HOBT) (0.025 g,0.184 mmol) were dissolved in DMF (2 mL), treated with 2,3-dichlorobenzylamine (0.025 mL, 0.184 mmol), and brought to pH 7 with Et3N (0.026 mL, 0.184 mmol). After stirring at ambient temperature for 18 h the mixture was concentrated to dryness, and the residue was partitioned between EtOAc and H2O, the organic layer separated, washed with aq satd NaHCO3, brine, and dried (Na2SO4). Filtration and concentration provided the title compound. 1H NMR (CD3OD) δ 7.1-7.5 (m, 18H), 4.53 (d, 1H, J=8 Hz), 4.26 (d, 1H,J=8 Hz), 3.64-3.76 (m, 1H), 2.96-3.14 (m, 2H), 2.52-2.66 (m, 1H), 2.1-2.5 (m, 5H), 1.6-1.9 (m, 3H), 1.45 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CCCCC3)nc3cc(Cl)ccc23)CC1
Yield: 11.8 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.4 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.56 mmol), and cyclohexylamine (286 μL, 2.4 mmol) are treated according to method E yielding 21 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(cyclohexylamino)quinoline which is treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (8 μL) and triethylamine (60 μL).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:27])[S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-(2-nitrobenzenesulfonylamino)piperidine-1-carboxylic acid tert-butyl ester (Preparation 73) (400 mg, 1.04 mmol) in DMF (10 mL) was added caesium carbonate (507 mg, 1.56 mmol) and the mixture stirred at rt for 40 min. Iodomethane (323 μL, 5.19 mmol) was added and the mixture stirred for 16 h. Solvent was removed in vacuo and the crude residue partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and washed with 1M HCl (2×20 mL), water (20 mL), then brine (2×20 mL) before being dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow powder. δH (d6 DMSO): 8.43 (2H, m), 8.01 (2H, m), 4.00-3.89 (3H, m), 2.83-2.67 (5H, m), 1.54-1.43 (2H, m), 1.39 (9H, s), 1.34-1.24 (2H, m).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([I:23])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:29]([O:24][C@@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([I:23])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[CH2:12]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)C[C@@H]1O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47 %

Procedure:
To a stirred solution of 18 (1.18 g; 2.52 mmol) in anhydrous THF (43 mL), 95% NaH powder (128 mg; 5.07 mmol) was added. The suspension mixture was stirred at room temperature for 45 min. Allyl bromide (240 μL, 2.79 mmol) was then added at 0° C. and the reaction was stirred at room temperature for another 14 h with exclusion of moisture. Saturated aqueous NaHCO3 (10 mL) was added at 0° C. and the reaction mixture was stirred for 10 min. After evaporation, the residue was dissolved in ethyl acetate (150 mL). The solution was then washed with saturated aqueous NaHCO3 and NaCl, and dried over anhydrous Na3SO4. After evaporation, the residue was purified by flash column chromatography using ethyl acetate as the eluent to afford 19 as white solid (601 mg; 47% yield) 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H, 6-H), 6.12 (dd, J=5.6, 8.0 Hz, 1H, 1′-H), 4.17 (m, 1H, 4′-H), 4.14 (m, 1H, 3′-H), 3.98-4.10 (m, 2H, CH3CH═CH3), 3.93 (dd, J=2.8, 11.5 Hz, 1H, one of 5′-H), 3.83 (dd, J=2.8, 11.5 Hz, 1H, one of 5′-H), 2.53-2.60 (ddd, J=1.7, 5.6, 13.6 Hz, 1H, one of 2′-H), 1.94-2.02 (ddd, J=5.9, 8.0, 13.6 Hz, 1H, one of 2′-H), 0.94 (s, 9H, C(CH3)3), 0.17 (s, 3H, one of SiCH3), 0.16 (s, 3H, one of SiCH3); 13C NMR (100 MHz, CD3OD) δ 165.4, 156.7, 147.7, 135.5, 117.2, 88.2, 87.0, 80.4, 70.9, 64.8, 57.3, 40.1, 26.7, 19.4, −4.7, −4.9; HRMS (FAB+) calcd for C18H31O4N3SiI (M+H+): 508.1129. found: 508.1123.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25](OC)([O:27]C)[CH3:26].[ClH:31]>C(#N)C.CCOCC.C(O)C>[ClH:31].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25](=[O:27])[CH3:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(C)(CBr)OC
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (7.45 g, 33.4 mmol), K2CO3 (5.5 g and bromo-2,2-dimethoxypropane (6.84 g, 37.6 mmol) in acetonitrile (200 ml) was heated and stirred at reflux for 4 hours. An additional charge of bromo-2,2-dimethoxypropane (5.1 g, 28 mmol) was added and the mixture was refluxed overnight. After being cooled to room temperature, the mixture was filtered, and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column (SiO2, 100 g; eluted with dichloromethane, DCM, and 1% CH3OH in DCM). The oil product thus obtained weighed 2.2 g (24%). The oil product was dissolved into ethanol (10 ml) then was treated with HCl in ether solution (1M, 9 ml) at room temperature. The crystals were collected, 2.08 g, m.p.=220°-223° C. dec.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:20])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].[I-].[Na+].CN(C=O)C>O>[NH2:19][C:10]1[C:9]2=[N:8][N:7]([CH3:20])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:25]3[C:21](=[O:31])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:26])=[C:18]2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cn1nc2c(N)nc3c(c2c1CCCCCl)CCCC3
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc2c(N)nc3c(c2c1CCCCN1C(=O)c2ccccc2C1=O)CCCC3
Temperature: 90 °C

Procedure:
A mixture of 1-(4-chlorobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinoline-4-amine (385 mg, 1.31 mmol), potassium phthalimide (362 mg, 1.96 mmol), sodium iodide (50 mg, 0.327 mmol), and DMF (2 mL) was heated at 90° C. for 4 hours. The reaction mixture was cooled to ambient temperature and then diluted with water (30 mL) while stirring in an ice bath. A precipitate was isolated by filtration to obtain 2-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1>CO>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:20]3[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=3)[CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2nccc(N)n2)CC1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCN(c2nccc(Nc3ncc(C#N)s3)n2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(4-acetylpiperazin-1-yl)pyrimidin-4-amine 4-4 (0.1 g, 0.45 mmol) was dissolved in dry TBF and then 1 equivalent of sodium hydride (0.036 g, 0.45 mmol) was added and this was stirred for 20 minutes at 25° C. then 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.065 g, 0.45 mmol) was added followed immediately by 1 more equivalent of sodium hydride. The reaction was then stirred at 100° C. for 3 hours. The reaction was cooled to 25° C. and methanol was added. This solution was loaded directly onto a silica column and eluted with DCM:MeOH:NH4OH (95:5:0.5). Fractions were combined and evaporated to yield the product, 4-5. Hi-Res MS: calc: 330.1132 found: 330.1137. 1H-NMR (DMSO): 8.33 ppm (s, 1H); 8.19 ppm (d, 1H); 6.34 ppm (d, 1H); 3.88 ppm (m, 2H); 3.80 ppm (m, 2H); 3.57 ppm (m, 4H); 2.07 ppm (s, 3H).
Reaction SMILES: C([O:8][C@H:9]([CH3:37])[C@@H:10]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:27]([O:29]CC1C=CC=CC=1)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[NH2:11])C1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[NH2:11][C@H:10]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[C@@H:9]([CH3:37])[OH:8]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)OCc1ccccc1)C(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)O)C(C)C)C(=O)O
Reaction time: 4 h
Yield: 85 %

Procedure:
One gram of benzyl O-benzylthreonylvalylleucinate hydrochloride is neutralized to provide benzyl O-benzylthreonylvalylleucinate. A hydrogenolysis mixture is prepared containing the benzyl O-benzylthreonylvalylleucinate, 0.5 grams of 10 percent palladium on charcoal per 0.01 mole of the material to be hydrogenated, and absolute ethanol. To the mixture is added 1.1 mole equivalents of acetic acid based on the benzyl ester. The mixture is hydrogenated for 4 hours. The catalyst is removed by filtration and the solvents are removed in vacuo. The residue is washed with anhydrous ether and recrystallized from an ethanol/ether mixture to provide 544 milligrams of the free peptide, threonylvalylleucine (85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:9][CH2:8]1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([F:49])=[C:31]([C:33]2[S:34][C:35]([NH:41]C(OC(C)(C)C)=O)=[C:36]([C:38](O)=[O:39])[N:37]=2)[CH:32]=1.C(OC(NC1SC=NC=1C(O)=O)=O)(C)(C)C>>[NH2:41][C:35]1[S:34][C:33]([C:31]2[CH:32]=[C:27]([Br:26])[CH:28]=[CH:29][C:30]=2[F:49])=[N:37][C:36]=1[C:38]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:25])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9][CH2:8]1)=[O:39]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(Br)ccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)OC(=O)Nc1scnc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Br)ccc3F)sc2N)c1N1CCC[C@@H](N)CC1

Procedure:
Following procedures from Examples 140, (R)-benzyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16 and the product of Example 27, 245-bromo-2-fluorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid, were converted to 308. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 8.45 (dd, J=6.7, 2.5 Hz, 1H), 7.66-7.55 (m, 1H), 7.48 (s, 2H), 7.43 (s, 1H), 7.36 (dd, J=11.2, 8.9 Hz, 1H), 3.65 (s, 4H), 3.21-2.93 (m, 7H), 1.84 (dd, J=8.2, 3.6 Hz, 3H), 1.72-1.39 (m, 3H). MS (ESI) m/z: 508.1/510.1 [M+H+].
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([O:11][C@H:12]1[CH2:31][C@@:30]2([CH3:32])[C@@H:23]([CH2:24][CH:25]=[C:26]2[C:27](=[O:29])[CH3:28])[C@H:22]2[C@H:13]1[C@:14]1([CH3:34])[C@@H:19]([CH2:20][CH2:21]2)[CH2:18][C@@H:17]([OH:33])[CH2:16][CH2:15]1)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]>[Pd].C(OCC)(=O)C>[CH2:1]([N:4]([CH2:8][C:9]([O:11][C@H:12]1[CH2:31][C@@:30]2([CH3:32])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[C:27](=[O:29])[CH3:28])[C@H:22]2[C@H:13]1[C@:14]1([CH3:34])[C@@H:19]([CH2:20][CH2:21]2)[CH2:18][C@@H:17]([OH:33])[CH2:16][CH2:15]1)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)C(C(C)=O)=CC[C@H]2[C@@H]2CC[C@H]3C[C@@H](O)CC[C@]3(C)[C@H]21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@@H](O)CC[C@]3(C)[C@H]21

Procedure:
11β-N,N-Dipropylaminoacetoxy-3β-hydroxy-5α-pregn-16-en-20-one (150 mg) was stirred with 5% palladium on charcoal (100 mg) in ethyl acetate (25 ml) at 20° under hydrogen. After 1 hour the catalyst was separated off using a Kieselguhr filter aid and the ethyl acetate was evaporated to leave a white solid. This was recrystallised from ethyl acetate in petroleum ether to give title compound as white crystals, m.p. 145 to 147.5 [α]D +85.2°. (89 mg).
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[C:10]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:42][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[C:10]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCNCC3)c2n1
Yield: 88.6 %

Procedure:
Reaction of the above carbamate (165 mg, 0.282 mmol) with an excess of TFA (2 mL) in CH2Cl2 (10 mL) at room temperature for 1.5 hrs, followed by treatment with aq. NH3 gave 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-9-(4-piperidinyl)-9H-purine (121 mg, 88%), which was used in the next step without further purification: 1H NMR (CDCl3) δ 7.87 (s, 1H), 7.81 (dd, J=8.4, 0.5 Hz, 1H), 7.48 (t, J=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.54 (tt, J=12.0, 4.1 Hz, 1H), 4.38 (br s, 4H), 4.07 (s, 3H), 3.88 (t, J=4.8 Hz, 4H), 3.30 (d, J=12.4 Hz, 2H), 2.86 (dt, J=12.4, 2.3 Hz, 2H), 2.20 (dd, J=11.8, 2.2 Hz, 2H), 2.04 (dq, J=12.3, 4.1 Hz, 2H).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].[C:21](=[O:23])=[O:22].Cl>O1CCCC1>[CH3:6][O:7][C:8]1[C:9]([NH:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: COc1ccccc1NC(=O)C(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)O)c1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
n-Butyllithium (1.6M solution in hexane; 200 ml, 0.32 mol) was added dropwise under nitrogen at −10° C. to a stirred solution of N-(2-methoxyphenyl)pivalamide (27.6 g, 0.133 mol) in tetrahydrofuran (600 ml), the mixture was allowed to warm to ambient temperature, stirred for a further 2 hours, then it was added to a large excess of crushed solid carbon dioxide. The mixture was allowed to warm to ambient temperature, 3M hydrochloric acid (200 ml) was added and the tetrahydrofuran was removed in vacuo. The resulting solid was collected by filtration and crystallised from acetonitrile to give 3-methoxy-2-pivalamidobenzoic acid (21 g; 63%) as a solid, m.pt. 117–120° C. Concentration of the liquor yielded a second crop (2.6 g; 8%).
Reaction SMILES: C1COCC1.[Si]([O:13][C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=4)=[CH:30][C:29]3=[O:43])=[CH:24][CH:23]=2)[CH2:15]1)(C(C)(C)C)(C)C>C(Cl)(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][O:34][C:31]2[CH:32]=[CH:33][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][N:16]4[CH2:17][CH2:18][C@@H:14]([OH:13])[CH2:15]4)=[CH:27][CH:26]=3)[C:29](=[O:43])[CH:30]=2)=[N:37][CH:38]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(CCOc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCN2CC[C@@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Tetra-n-butylamnunium fluoroide (1.0M THF solution, 0.924 mL, 0.92 mmol) was added to THF (2 mL) solution of 1-{4-[2-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-pyrrolidinyl)ethoxy]phenyl}-4-[(5-chloro-2-pyridinyl)methoxy]-1H-pyridin-2-one (257.0 mg, 0.46 mmol), and stirred at room temperature for 3 hours. Chloroform was added to the reaction liquid, which then was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on high performance liquid chromatography (YMC-Pack™ pro C-18, 0.1% THF solution: 0.1% TFA acetonitrile solution=10→95%), and the resulting crude title compound was recrystallized fronm ethyl acetate-heptane mixed solvent to provide the title compound (103.1 mg, 50%).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10]C(=O)C)[O:7][C@@H:6]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[S:19])[NH:17][C:15]2=[O:16])[CH2:5]1)=[N+:2]=[N-:3]>O1CCOCC1.[NH4+].[OH-].CCOCC>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:14]2[CH:22]=[C:20]([CH3:21])[C:18](=[S:19])[NH:17][C:15]2=[O:16])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=S)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=S
Reaction time: 18 h

Procedure:
3'-Azido-3'-deoxy-5'-O-acetyl-4-thiothymidine (0.25 g; 0.76 mMol, Example 21) was dissolved in a mixture of 5 mL of dioxane and 5 mL of conc. NH4OH and stirred for 18 hrs. The solvent was removed in vacuo and the residue applied to a silica gel column followed by elution with CHCl3 /EtOAc (3:1 v/v). The appropriate fractions were combined and the solvent removed in vacuo to yield a yellow oil which was dissolved in Et2O, forming crystals upon concentration: 0.16 g (0.56 mMol; 74%); m.p.=116°-118° C.