Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[C:7](#[N:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(OCC)=O.CC(C)([O-])C>C1(C)C=CC=CC=1.O.CCOCC.O1CCCC1>[CH:2]([CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]#[N:14])=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCC#N
Agent: [K+]
Solvent: CCOC=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC(C#N)C=O
Reaction time: 5 h
Yield: 76.3 %

Procedure:
A solution of potassium tert-butoxide (18.9 g) in a mixed solvent system of tetrahydrofuran (150 ml) and toluene (100 ml) was heated to 75° . A solution of heptanonitrile (11.2 g) and ethyl formate (24 ml) in toluene (50 ml) was then added dropwise to the warm tert-butoxide solution. The reaction was stirred for 5 hours at 75° then cooled with an ice bath. Ether was added to the mixture and then water. The layers were separated. The aqueous phase was washed once with ether then acidified to a pH of about 3 with aqueous hydrochloric acid (6N). The aqueous phase was saturated with sodium chloride then extracted twice with ether. The combined ether extracts were washed with brine, dried (MgSO4) and concentrated to leave the title product as a yellow oil (10.7 g, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].CO.[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:19]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OC)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.04 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 2.2 mmol methanol and 2.34 mmol triphenylphosphine in 10 ml THF was added 2.24 mmol di-tert-butyl azodicarboxylate and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane) to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18]S([O-])(=O)=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(N(CC)CC)C.[CH2:30]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:30]([CH:37]1[CH2:42][CH2:41][N:40]([CH2:18][C:16]2[N:17]=[C:12]([C:4]3[S:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:2](=[O:1])[N:3]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1nc(-c2cccc(CN3CCC(Cc4ccccc4)CC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 4-benzylpiperidine (0.17 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.25 g, 67%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:40])(C)C.CCOCC>CC(CC)=O>[ClH:40].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(c1ccc(F)cc1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(4-fluorobenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one (254 mg, 0.9 mmol) was dissolved in ethyl methyl ketone (2.0 mL), water (5 μL), TMSCl (77 μL), and ether (20 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(4-fluorobenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 242 mg (88%).
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][C@@H:7]([NH:32][CH2:33][C@@H:34]2[CH2:38][C@@H:37]([OH:39])[CH2:36][N:35]2C(OC(C)(C)C)=O)[C:8]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH:13]([N:18]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1.Cl>C(OCC)C>[Cl:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][C@H:7]([C:8]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH:13]([N:18]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])[CH2:14]3)=[O:9])[NH:32][CH2:33][C@@H:34]2[CH2:38][C@@H:37]([OH:39])[CH2:36][NH:35]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC[C@@H]1C[C@@H](O)CN1
Yield: 75.2 %

Procedure:
0.28 g of tert-butyl (2S,4R)-2-({[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]-amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}-methyl)-4-hydroxypyrrolidine-1-carboxylate is dissolved in 5 ml of diethyl ether, and then 2.7 ml of 2N hydrochloric acid in diethyl ether are added. Trituration, rinsing with diethyl ether, and filter-drying of the precipitate obtained are carried out, which precipitate is chromatographed on silica gel, elution being carried out with a 90/10/1 mixture of dichloromethane, methanol and aqueous ammonia. 0.18 g of N-[8-(4-chloro-N-{[(2S,4R)-4-hydroxypyrrolidin-2-yl]methyl}-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea is obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl.[Cl-].[Na+].O>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[C:2]([F:1])=[C:10]([F:11])[C:9]([F:12])=[C:8]([F:13])[C:7]=1[F:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A solution of 2,3,4,5,6-pentafluorobenzoic acid (15.25 g, 71.9 mmol), 4-dimethylaminopyridine (4.4 g, 36.0 mmol) and benzyl alcohol (7.4 mL, 71.5 mmol) in dichloromethane (150 mL) is cooled to 0° C. under an inert atmosphere. 1-[3-(Dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (16.7 g, 87.1 mmol) is added and the mixture stirred at 0° C. for 2 hours. The mixture is warmed to ambient temperature, stirred for 24 hours, and then poured into brine. The mixture is extracted with chloroform and the organic phase washed with NaHCO3, dried over Na2SO4, filtered and concentrated under vacuum to yield the title compound as a white solid (16.7 g). This material is used without further purification. 1H NMR (CDCl3): δ 7.49–7.27 (m, 5H), 5.40 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[N:62]=[C:61]([N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1)[CH:60]=[CH:59]2>ClCCl>[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[N:62]=[C:61]([N:66]1[CH2:67][CH2:68][N:69]([C:19](=[O:20])[CH2:18][O:17][CH:14]3[CH2:15][CH2:16][CH:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:23])([F:24])[F:25])[CH:6]=4)[CH2:12][CH2:13]3)[CH2:70][CH2:71]1)[CH:60]=[CH:59]2
Reactant: Fc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(F)ccc3n2)CC1
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl) oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (79.1 mg, 0.41 mmol), HOBt (55.9 mg, 0.41 mmol), triethylamine (83.7 mg, 0.83 mmol) and 6-fluoro-2-(piperazin-1-yl)quinoline (70.2 mg, 0.30 mmol) at room temperature. After stirred overnight, the reaction mixture was then diluted with dichloromethane (100 ml) and washed with water (2×100 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% methanol in dichloromethane to afford 1-[4-(6-fluoroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (80 mg, 48%); (ES, m/z): [M+H]+ 576.20; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J=8.8 Hz, 1H), 7.94-7.99 (m, 1H), 7.72-7.78 (m, 1H), 7.31-7.37 (m, 2H), 7.02 (t, J=8.0 Hz, 1H), 6.87 (s, 1H), 6.64 (dd, J=2.4 Hz, 9.2 Hz, 1H), 4.48 (d, J=7.6 Hz, 1H), 4.28 (s, 2H), 3.75-3.81 (m, 7H), 3.41-3.49 (m, 2H), 2.17-2.19 (m, 4H), 1.50-1.58 (m, 2H), 1.28-1.36 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:15][CH2:16][S:17][CH3:18])=[N:6]1)=[O:4]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][S:17][CH3:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)C1Cc2ccccc2C(CCSC)=N1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)c1cc2ccccc2c(CCSC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
1.297 g (7 mmol) of copper acetate was added to a solution of 923 mg (3.5 mmol) of 1-(2-methylsulfanyl-ethyl)-3,4-dihydro-isoquinoline-3-carboxylic acid methyl ester in 10 mL of dichloromethane, stirring at room temperature overnight. This reaction mixture was concentrated and purified by column chromatography on silica gel to give 266 mg (29%) of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid methyl ester. LCMS: 262 (M+1)+.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[Cl:16][CH2:2][CH2:3][C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: OCCc1ccc2c(n1)NCCC2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCCc1ccc2c(n1)NCCC2
Yield: 90 %

Procedure:
7-(2-hydroxyethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (5.00 g) was added to thionyl chloride (25 mL) and refluxed for 12 hour in benzene (100 mL). The resulting solution was concentrated and the red oil was dissolved in CH2Cl2 and washed with NaHCO3 (satd). The CH2Cl2 layer was extracted, dried with Na2SO4, and concentrated in vacuo to afford 4.99 g (90%) of a tan solid. 1H NMR (DMSO-d6) δ 7.06 (d, 1H), 6.35 (br s, 1H), 6.33 (d, 1H), 3.86 (t, 2H), 3.25 (m, 2H), 2.87 (t, 2H), 2.62 (t, 2H), 1.75 (pentet, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>C(Cl)Cl.[Cu](I)I.CCOC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: Clc1cnccn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cnccn2)c1
Temperature: 115 °C
Yield: 113.2 %

Procedure:
A mixture of (S)-[1-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1 g, 4.2 mmol), 2-chloro-pyrazine (0.58 g, 5.1 mmol), potassium carbonate (powder, 1.4 g, 10.1 mmol), copper iodide (325 mesh powder, 0.6 g, 3.2 mmol) and pyridine (5 mL) was heated at 115° C. for 24 h. CH2Cl2 (100 mL) was added, and the reaction mixture was diluted with CH2Cl2 (100 mL), filtered through celite, and rinse with CH2Cl2 (2×50 mL). The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with 1:1/Hexane:EtOAc to give the title product (1.5 g, quantitative yield).
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[C:39]([C:33]1[CH:34]=[N:35][C:36]2[C:31]([C:32]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=1)=[CH:30][C:29]([NH:28][C:10](=[O:12])[C:9]#[C:8][CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:38][CH:37]=2)#[N:40]
Reactant: COc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: O=C(O)C#CCN1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cccc(Nc2c(C#N)cnc3ccc(NC(=O)C#CCN4CCCCC4)cc23)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Partially dissolved 1.21 (7.22 mmol) 4-piperidino-2-butynoic acid in 100 ml THF and chilled to 0° C. under N2. Added 955 μl (8.67 mmol) N-methylmorpholine and 750 μl (5.78 mmol) isobutyl chloroformate. Stirred for 40 minutes and added a solution of 840 mg (2.89 mmol) 6-amino-4-[(3-methoxyphenyl)amino]-3-quinolinecarbonitrile dissolved in 10 ml hot pyridine. At 2 hours, poured into ice water and made basic with saturated sodium bicarbonate. Extracted with ethyl acetate, dried with sodium sulfate, and stripped down to a small volume, which was loaded onto a column of silica gel. Eluted with 10% methanol/ethyl acetate, stripped solvent of desired fractions, and dried in vacuo, giving 970 mg of green solid: mass spectrum (electrospray m/e): M+H=440.1.
Reaction SMILES: NCCCCCC([O:9][C:10]1[C:11](=[CH:16][CH:17]=[C:18](CN)[CH:19]=1)[C:12]([NH:14][OH:15])=[O:13])=O.Cl>C([O-])(O)=O.[Na+]>[C:12]([NH:14][OH:15])(=[O:13])[C:11]1[C:10](=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:9]
Reactant: NCCCCCC(=O)Oc1cc(CN)ccc1C(=O)NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NO)c1ccccc1O

Procedure:
SHA-Sepharose 4B was prepared by mixing 130 mg of (6-aminohexanoyl)-4-aminomethylsalicylhydroxamic acid (SHA-Z-NH2), dissolved in 30 mL 0.2M NaHCO3, with 6.5 g HCl washed CNBr activated Sepharose 4B (Pharmacia) overnight at room temperature. After the coupling reaction, 2 mL 0.5M Tris, pH 8.5 were added and the gel slurry mixed at room temperature for 1 hour, and washed with water, 0.5M NaCl, and water again. The resulting SHA-Sepharose 4B was suspended in 30 mL of 20% ethanol, and stored at 4° C.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[N:32]=[C:33]([C:44]4[C:49]([F:50])=[CH:48][CH:47]=[C:46]([O:51][CH3:52])[C:45]=4[F:53])[S:34][C:35]=3[NH:36]C(OC(C)(C)C)=O)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[NH2:36][C:35]1[S:34][C:33]([C:44]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([O:51][CH3:52])[C:45]=2[F:53])=[N:32][C:31]=1[C:29]([NH:28][C:12]1[C:13]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH2:20])[CH2:15]2)=[C:8]2[CH2:7][CH2:6][CH:5]([OH:4])[C:9]2=[N:10][CH:11]=1)=[O:30]
Reactant: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)c(NC(=O)OC(C)(C)C)s2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](N)C3)CCC4O)c(N)s2)c1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluoro-3-methoxyphenyl)-1,3-thiazol-4-yl]carbonyl}amino)-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (3.2 mg, 0.0042 mmol), MeOH (50 μL), THF (25 μL) and 1.0 M aq. NaOH (27 μL, 0.027 mmol) was stirred at room temperature for 20 min. The organic solvents were removed under reduced pressure to give a crude intermediate, which was dissolved in DCM (0.04 mL), and then TFA (0.043 mL, 0.56 mmol) was added. The reaction mixture was stirred at room temperature for 20 min. After concentration under reduced pressure, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give both diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)) the diastereoisomers had the following properties:
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33].N1CCOCC1>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: N#CCCCCBr
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
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: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)n(CCCCC#N)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (4.0 g, 13.5 mmol) in DMF (100 ml) was treated with caesium carbonate (4.83 g, 14.8 mmol) and 5-bromopentanenitrile (1.73 ml, 14.8 mmol). The mixture was heated at 50° C. in a nitrogen atmosphere for 19 h and then cooled. The mixture was then degassed by the repeated successive application of a vacuum and then nitrogen pressure. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.94 mmol) and morpholine (11.8 ml, 136 mmol). The mixture was stirred in a nitrogen atmosphere for 3 h and then partitioned between EtOAc and 2M aqueous hydrochloric acid. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to reveal a yellow, oily residue. This was dissolved in MeOH, divided equally into four portions and each portion applied to a 20 g aminopropyl SPE which was then washed through with MeOH. The desired product was eluted from the cartridge with a 5% v/v solution of AcOH in MeOH. The product-containing fractions were combined and concentrated to yield the title compound as a pale yellow solid (4.03 g, 88%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH2:9][N:8]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:13][CH2:12][C:11]=2[CH3:14])=[CH:20][CH:19]=1)=[O:31]
Reactant: CCOC(=O)Cl
Reactant: CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)C1
Reaction time: 3 h
Yield: 97 %

Procedure:
The Compound 11 (31 mg, 0.074 mmol) was dissolved in methylene chloride (2 ml) at room temperature. Ethyl chloroformate (14 ul, 2 eq) was added to the solution and the reaction was stirred for 3 hours. The solvent was removed and the crude mixture was purified by flash chromatograph with ethyl acetate/hexane to produce 28.4 mg (97% yield) of Compound 12.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14]Br)[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)[C@H]1C[C@@H](CCBr)CN1C(=O)OC(C)(C)C
Product: CCOP(=O)(CC[C@@H]1C[C@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)OCC

Procedure:
A mixture of 0.60 g of cis methyl N-t-butoxycarbonyl-4-(2-bromoethyl)pyrrolidine-2-carboxylate and 3 ml triethyl phosphite is refluxed for 2 hours. The excess triethyl phosphite is distilled off under vacuum and the residue is flash chromatographed with methylene chloride/methanol (95:5) to afford cis methyl N-t-butoxycarbonyl-4-(2-di-ethylphosphonoethyl)pyrrolidine-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CCOCC.I[C:22]1[N:23]=[CH:24][N:25]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH:26]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:22]3[N:23]=[CH:24][N:25]([CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)[CH:26]=3)[S:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cnc(I)c2)CC1
Reactant: Clc1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(CCn2cnc(-c3cc4nccc(Cl)c4s3)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (2.95 g, 17.39 mmol) in THF (60 ml) at −15° C. was added n-BuLi (2.5M, 6.96 ml, 17.39 mmol). After 30 min, a solution of ZnCl2 in Et2O (1M, 17.39 mL, 17.39 mmol) was added at −15° C. and the reaction mixture was warmed to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.268 g, 0.232 mmol) and 304 (4.71 g, 11.59 mmol) in THF (18 ml) was added and the mixture was heated to reflux for 1 h then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with a mixture of MTBE/Hexane, to afford the title compound 305 (3.75 g, 8.37 mmol, 72% yield) as a beige solid. MS (m/z): 448.46 (M+H).
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1C1=NC(C)(C(C)C)C(=O)N1)OCO2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C1(C)N=C(c2c(C(=O)O)ccc3c2OCO3)NC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Methyl 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3,4-(methylenedioxy)benzoate (6.00 g, 16.9 mmol) is added to 7.5N sulfuric (100 mL), stirred for 15 hours at reflux temperature, cooled to 0° C. and treated with 6N sodium hydroxide to pH 4. The resultant mixture is continuously extracted with ethyl acetate overnight, and the organic layer is concentrated in vacuo to afford the title product as a white solid, 3.40 g (59.1%), mp 172°-176° C.