Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:53])[NH:22][C@H:23]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:24][N:25]1[C:30](=[O:31])[C:29](Br)=[C:28]([CH3:33])[N:27]([CH2:34][C:35]2[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:36]=2[F:45])[C:26]1=[O:46])([CH3:19])([CH3:18])[CH3:17]>C(#N)C>[C:16]([O:20][C:21](=[O:53])[NH:22][C@H:23]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH2:24][N:25]1[C:30](=[O:31])[C:29]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]([CH2:14][OH:15])[CH2:10]2)=[C:28]([CH3:33])[N:27]([CH2:34][C:35]2[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:36]=2[F:45])[C:26]1=[O:46])([CH3:17])([CH3:18])[CH3:19]
Reactant: OCC1CNCCN1Cc1ccccc1
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: CC#N
Product: Cc1c(N2CCN(Cc3ccccc3)C(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
(1-Benzyl-piperazin-2-yl)-methanol (200 mg, 0.97 mmol), {(R)-2-[5-bromo-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.083 mmol), and acetonitrile (1 mL) were placed in a microwave vessel and stirred at 120° C. for 3 hrs with microwave irradiation. After concentration of the solution, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/1/1) and dried in a vacuum to afford 20 mg of a colorless oil (yield 33%) . 1H NMR (300 MHz, CDCl3) δ 1.37 (9H, s), 2.23 (1H, m), 2.34 (3H, s), 2.41-2.66 (2H, m), 2.85 (1H, m), 3.16 (1H, m), 3.49 (1H, m), 3.72 (1H, m), 3.93-4.15 (3H, m), 4.21 (1H, m), 5.03 (1H, m), 5.42 (2H, dd), 5.74 (1H, m), 7.21 (2H, m), 7.18-7.26 (10H, m), 7.54 (1H, d)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:36])[O:14][CH2:15][C@@H:16]([N:22]([CH3:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[Cl:34])=[O:24])[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:5]2.CO>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:36])[O:14][CH2:15][C@@H:16]([N:22]([CH3:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[Cl:34])=[O:24])[CH2:17][C@H:18]([OH:21])[CH2:19][OH:20])=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(O)CO
Solvent: ClCCl
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)C[C@H](O)CO
Reaction time: 0.17 h
Yield: 14.3 %

Procedure:
A solution of crude (2S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,5-dihydroxypentyl 6-fluoroisoquinolin-3-ylcarbamate (0.07 g) in DCM (1 mL) was loaded onto a TLC Silica gel 60 F254 (20×20 cm) plate and developed with a mixture of DCM and methanol (20:1). The top layer was collected and stirred in methanol (50 mL) for 10 min. After filtration, the filtrate was concentrated to give (2S,4S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,5-dihydroxypentyl 6-fluoroisoquinolin-3-ylcarbamate (0.01 g, 14.3%). LRMS (M+H+) m/z 523.2. The same process was applied to the bottom layer to give (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,5-dihydroxypentyl 6-fluoroisoquinolin-3-ylcarbamate (27 mg, 38.6%). LRMS (M+H+) m/z 523.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14](=[O:20])[CH2:15][C:16](OC)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[OH:20][CH:14]([CH2:15][CH2:16][OH:17])[CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCCC(O)CCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 5-(benzyloxycarbonylamino)-3-oxopentanoate (4.5 g, 15.3 mmoles) is dissolved in anhydrous tetrahydrofuran (25 mL) and this solution is added slowly dropwise to an ice-cooled solution of lithium borohydride in anhydrous tetrahydrofuran (2 M, 25 mL, 50 mmoles). When the addition is complete, the cooling bath is removed and the reaction is stirred at ambient temperature for 16 hours. The clear, colorless solution is again cooled in an ice bath, and aqueous hydrochloric acid (1 M, 50 mL) is added slowly dropwise to decompose the excess reducing agent (gas is evolved). When a homogeneous solution is obtained, the mixture is concentrated to remove tetrahydrofuran. Ethyl acetate (100 mL) is added; the mixture is shaken well and poured into a separatory funnel. The layers are allowed to separate and the bottom aqueous layer is drawn off. The aqueous layer is then washed twice more with ethyl acetate (100 mL each), and the combined ethyl acetate solutions are washed with saturated aqueous sodium chloride (50 mL). The ethyl acetate solution is then dried over anhydrous sodium sulfate, filtered and evaporated to a pale brown syrup. The crude product is purified on silica gel (200 mL bed volume) eluting with ethyl acetate (500 mL) then ethyl acetate:methanol (99:1 [v/v], 500 mL then 95:5 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a pale yellow oil. The oil is dried well in vacuo. The yield is 3.6 g (92%). The oil solidifies on standing at 4° C.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:19]=3)[C:14]([OH:29])=[C:13]([C:30](OC)=[O:31])[C:12]2=[O:34])=[CH:7][CH:6]=1)=[O:4].[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][C:41]1=[O:45]>CO>[CH3:1][N:2]([CH3:35])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH:19]=3)[C:14]([OH:29])=[C:13]([C:30]([NH:36][CH2:37][CH2:38][CH2:39][N:40]3[CH2:44][CH2:43][CH2:42][C:41]3=[O:45])=[O:31])[C:12]2=[O:34])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(C(=O)N(C)C)cc2)c1=O
Reactant: NCCCN1CCCC1=O
Solvent: CO
Product: CN(C)C(=O)c1ccc(-n2c(=O)c(C(=O)NCCCN3CCCC3=O)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1
Yield: 80 %

Procedure:
In a similar manner to that described in example 196, from methyl 1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.0421 mmol), 1-(3-aminopropyl)-2-pyrrolidinone (0.05 mL), and methanol (2 mL), was prepared 1-{4-[(dimethylamino)carbonyl]phenyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (20 mg, 80% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.04 (t, J=6 Hz, 1 H), 8.51 (d, J=1.6 Hz, 1 H), 7.65 (d, J=8.4 Hz, 2 H), 7.28 (d, J==8.4 Hz, 2 H), 7.03-6.99 (m, 2 H), 6.96-6.91 (m, 2 H), 6.79 (d, J=1.6 Hz, 1 H), 3.94 (s, 2 H), 3.45-3.33 (m, 6 H), 3.16 (s, 3 H), 3.06 (s, 3 H), 2.36 (t, J=8 Hz, 2 H), 2.05-1.97 (m, 2 H), 1.87-1.80 (m, 2 H); MS m/z 586 (M+1).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].B.CSC.O>C1COCC1>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: B
Solvent: O
Solvent: CSC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC1CO
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
N-Carbobenzyloxy-L-proline (0.048 moles, 12.0 g) was dissolved in 50 ml THF and cooled to 0° C. Borane-methyl sulfide complex (0.05 moles, 25 ml of 2M in THF) was added dropwise. The reaction was stirred for 16 hours at room temperature and then cooled to 0° C. water (50 ml) was added dropwise. The solution was filtered. The solid was washed with ethyl acetate. The organic solutions were combined, washed with water, dried over sodium sulfate and concentrated to yield 10.3 g of N-carbobenzyloxy-2-hydroxymethyl pyrrolidine. N-carbobenzyloxy-2-hydroxymethyl pyrrolidine (0.038 moles, 9.0 g) and triethylamine (0.076 mole) were dissolved in 150 ml of chloroform. Tosyl chloride (0.0475 moles, 9.05 g) was added portionwise followed by dimethylaminopyridine (200 mg). The solution was stirred overnight at room temperature. Chloroform was added. The solution was washed with water, dried over sodium sulfate, and concentrated. The resulting tosylate (0.0385 moles, 15.0 g) and sodium cyanide (0.048 moles, 2.35 g) were dissolved in 150 ml DMSO. The reaction was heated to reflux until completion as measured by thin layer chromatography. The reaction was cooled; water was added. The intermediate was extracted with ethyl acetate and concentrated to yield 9.56 g of 2-pyrrolidineacetonitrile. The nitrile was hydrolyzed by dissolving in 150 ml ethanolic HCl and slowing adding water to the solution. The solution was then concentrated in vacuo. Ethyl acetate and sodium bicarbonate were added. The ethyl acetate solution was concentrated. The residue dissolved in ethyl acetate, filtered and concentrated. The resulting acetate was chromatographed on silica gel eluted with a gradient of 5.0-100% ethyl acetate in hexane followed by a gradient of 0-20% ethanol in ethyl acetate to yield 4.35 g of ethyl 2-pyrrolidineacetate. (MS)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.Cl.O1CCOCC1>>[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:33]([NH:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)NCCCC(=O)OC(C)(C)C)CCCC3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)NCCCC(=O)O)CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-tert-butyl 4-(1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxamido)butanoate 2,2,2-trifluoroacetate (2.6 mg, 4.11 μmol) was added 4M hydrogen chloride in dioxane (0.103 mL, 0.411 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated to give the title compound. LCMS m/z=463.4 [M+H]+.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[NH2:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>>[CH2:1]([S:5]([NH:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)Nc1cc(C(=O)Nc2ccccc2)ccc1OC
Yield: 92 %

Procedure:
Prepared according to the procedure described for Example 128 using 1-butanesulfonyl chloride (0.47 g, 3.0 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) to afford the product (1.0 g); m.p. 182-183° C. after recrystallization from ethanol.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:18]1OCCOCCOCCOCCOC1.IC>O1CCCC1.CO>[CH3:18][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1
Reactant: C1COCCOCCOCCOCCO1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl (trans-4-hydroxycyclohexyl)carbamate (1.0 g, 4.6 mmol) in tetrahydrofuran (20 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 24 mg, 6.4 mmol) and 15-crown-5 ether (965 μL) for 30 minutes under cooling with ice and then with iodomethane (289 μL) at room temperature for 1 hour. Methanol (2 mL) was added to the reaction mixture, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/1 (v/v)) to give the title compound (708 mg, yield 67%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][CH3:11])=[CH:6][N:7]=1
Reactant: CCI
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)nc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromopyridin-3-ol (7.58 g), iodoethane (5.23 mL), potassium carbonate (9.03 g), and DMF (80 mL) was stirred at 60° C. for 3 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (7.58 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3]([F:20])([F:19])[C:4]([F:18])([F:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O.[BrH:26].S(=O)(=O)(O)O>O>[Br:26][CH:5]([C:4]([F:18])([F:17])[C:3]([F:20])([F:19])[C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Br
Reactant: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCCCC(Br)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C

Procedure:
To a mixture of 19.52 g of 11-(nonafluorobutyl)-1-undecanol and 200 mL of 48 weight percent hydrobromic acid was slowly added 20 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 24 hr and poured into 1 liter of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solution was concentrated to an amber liquid, which was eluted through 3 inches of silica with hexanes. Concentration of the eluent yielded a light amber liquid, and bulb-to-bulb distillation gave 19.82 g of 1-bromo-1-(nonafluorobutyl)undecane as a clear, colorless liquid, b.p. 120-170° C. at 0.06 torr (8 Pa).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[Br:11]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([Br:11])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1csc(N)n1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1nc(N)sc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
2-Amino-4-[(1,1-dimethyl)ethyl]thiazole (compound of Example 181(1); 0.87 g, 5.6 mmol) was dissolved in carbon tetrachloride (9 mL). N-Bromosuccinimide (1.00 g, 5.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture. The insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (1.23 g, 93.7%) as an yellowish gray powder.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:70])[C@@H:64]([NH2:69])[CH2:65][O:66][CH2:67][CH3:68])[CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]>CN(C=O)C.C(Cl)CCl>[CH2:50]([O:54][C:55]([N:57]1[CH2:58][CH2:59][N:60]([C:63](=[O:70])[C@@H:64]([NH:69][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:29])[CH2:65][O:66][CH2:67][CH3:68])[CH2:61][CH2:62]1)=[O:56])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)COCC)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](COCC)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 75 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 5 ml DMF were added 37 mg HOAt, 53 mg EDC, 0.13 ml DIPEA and 55 mg 4-((S)-2-Amino-3-ethoxy-propionyl)-piperazine-1-carboxylic acid butyl ester. After stirring for 12 h it was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 86 mg MS (ES+): m/e=696.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:7][CH2:8][CH3:9])=[CH:5][CH:6]=1.[CH2:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([F:25])[C:22](B(O)O)=[C:21]([F:29])[CH:20]=2)=[CH:15][CH:14]=1)[CH2:11][CH3:12].P([O-])(O)(O)=O.[Na+].O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])(O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[F:25][C:23]1[CH:24]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)[CH:20]=[C:21]([F:29])[C:22]=1[C:2]1[S:3][C:4]([CH2:7][CH2:8][CH3:9])=[CH:5][CH:6]=1
Reactant: CCCc1ccc(Br)s1
Reactant: CCCc1ccc(-c2cc(F)c(B(O)O)c(F)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2cc(F)c(-c3ccc(CCC)s3)c(F)c2)cc1

Procedure:
5.0 g (24.4 mmol) of 2-bromo-5-propylthiophene, 7.40 g (26.8 mmol) of 4′-propyl-3,5-difluoro-4-biphenylboronic acid and 2.82 g (2.44 mmol) of tetrakis(triphenylphosphine)palladium(0) are initially introduced in 160 ml of toluene. A solution of 5.85 g (48.8 mmol) of sodium dihydrogenphosphate and 13.8 g (97.5 mmol) of disodium hydrogenphosphate dodecahydrate in 50 ml of water is added, and the mixture is heated under reflux for 19 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with toluene. The combined organic phases are washed with water and sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane). Further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-(3,5-difluoro-4′-propylbiphenyl-4-yl)-5-propylthiophene (PUS-3-3) as a colourless solid (m.p. 64° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:37]=[CH:36][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:31])[CH2:29]Br)[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.[K]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:37]=[CH:36][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:31])[CH2:29][N:42]3[C:41](=[O:43])[C:40]4=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]4[C:38]3=[O:48])[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CBr)c3ccccc32)cc1)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
(3aR*,10aS*)-9-[4-(Benzyloxycarbonylamino)benzyl]-4-(bromoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][l,4]diazepin-10(1H)-one (496 mg, 0.88 mmol) and potassium phthalimide (172 mg, 0.93 mmol) were suspended in DMF (3 mL) and the suspension was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with 3 portions of chloroform. The pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to provide 495 mg (yield 89%) of the title compound. m.p. 144°-147° C.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][C:8]2[C:9]([C:30]([O:32]C)=[O:31])=[N:10][C:11]([O:14][CH:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:16][C:17]3[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][C:8]2[C:9]([C:30]([OH:32])=[O:31])=[N:10][C:11]([O:14][CH:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:16][C:17]3[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(OC(Cc2cncn2C)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cncc1CC(Oc1ccc(CCc2ccc(F)cc2)c(C(=O)O)n1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of methyl 3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyridin-2-carboxylate (1.56 g), sodium hydroxide (0.65 g), water (12 ml) and methanol (80 ml) was heated at reflux for 16 hours and then cooled to ambient temperature. The mixture was concentrated under reduced pressure, 1M citric acid (17 ml) added and the mixture extracted with 10% methanol/dichloromethane (1×50 ml, 2×30 ml). The extracts were dried and concentrated under reduced pressure to give 3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyridin-2-carboxylic acid as a pale yellow foam (1.22 g).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[H-].[Na+].[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[CH2:13][CH3:14]>O1CCCC1>[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:17])[CH2:13][CH3:14]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CCCSc1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSc1ncn(C(=O)N(CCC)CCC)n1
Reaction time: 1 h

Procedure:
A solution of 35.75 g. 3-propylthio-1,2,4-triazole in 150 ml. dry tetrahydrofuran was added dropwise to a stirred suspension of sodium hydride in mineral oil (14.4 g. of 50% suspension; 7.2 g. sodium hydride). The resulting mixture was refluxed with stirring for 1 hour. Heating was discontinued, and 40.9 g. dipropylcarbamoyl chloride was added dropwise to the stirred mixture, causing the evolution of heat with consequent refluxing. The reaction mixture was refluxed with stirring overnight, cooled, and filtered to remove sodium chloride formed in the reaction. The filtrate was distilled under reduced pressure to remove solvent, and the residual oil was dissolved in methylene dichloride. The resulting solution was washed successively with 0.5N sodium hydroxide solution, water, and finally 0.5N hydrochloric acid. The washed solution was distilled under reduced pressure to give 1-dipropylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 128° - 120° C./0.1 mm. Elemental analysis satisfactory.