Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>CN1CCCC1=O.O>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([S:8][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:29]5[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=5)=[O:31])[CH:7]=[CH:6][CH:5]=4)=[N:14][N:13]3[CH:15]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (195 mg, 0.6 mmol) in N-methylpyrrolidone (3.0 mL) was added 1,3-dimethylpyrazole-5-carbonyl chloride (159 mg, 1.0 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and precipitated from methanol to give the title compound (245 mg, 91%) as a white powder.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([NH:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:12])[CH3:10])(OC(C)(C)C)=O.[ClH:19]>C(O)(=O)C.O1CCOCC1>[ClH:19].[CH3:1][NH:8][C@@H:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[CH3:10]
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CN[C@H](C)C(=O)NCC(=O)O

Procedure:
26.0 Grams of methyl Boc-D-alanylglycinate is dissolved in 340 ml of acetic acid, and 170 ml of a 6 N solution of hydrogen chloride in dioxane is added to the solution. The reaction mixture is allowed to stand for ten minutes and then the solvent is removed under vacuum. The residue is triturated with diethyl ether. The resulting white precipitate is filtered and washed with diethyl ether to afford methyl-D-alanylglycinate hydrochloride.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[NH:15][C:14]1=[O:24].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[NH:15][C:14]1=[O:24])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@@H]1C(=O)N[C@@H]1CCc1ccco1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CCc1ccco1)OCc1ccccc1
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A solution of benzyl chloroformate (5.4 mL, 0.0378 mol) in methylene chloride (10 mL) was added dropwise during 0.25 hr to a stirred, cooled (ice/H2O bath) of (3S,4R)-3-amino-4-[2-(2-furyl)ethyl]azetidin-2-one (6.82 g, 0.0378 mol) and diisopropylethylamine (6.6 mL, 0.0378 mol) in methylene chloride (75 mL). Stirring was continued with cooling for 2 hr and then for 0.5 hr at ambient temperatures. The mixture was diluted with additional methylene chloride and was sequentially washed with H2O, dilute hydrochloric acid, H2O, dilute aqueous NaHCO3, H2O and saturated NaCl. The solution was dried over MgSO4 and concentrated. The residue was crystallized from ethyl acetate to afford the title compound (7.05 g, 60% yield) as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]3[C:13]([NH2:20])=[N:14][CH:15]=[C:16]([CH:18]=[CH2:19])[N:17]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N-]>C1(C)C=CC=CC=1>[NH2:20][C:13]1[N:14]=[CH:15][C:16]([CH:18]2[CH2:19][CH:23]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:17][C:12]=1[C:10]1[O:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][N:9]=1
Reactant: C=Cc1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 110 °C

Procedure:
To a vial charged with 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-vinyl-pyrazin-2-amine (26 mg, 0.01 mmol) under an atmosphere of nitrogen at room temperature was slowly added a solution of ethyl 2-diazoacetate (34 mg, 31 μL, 0.1 mmol) in toluene (350 μL) over a period of 10 min. The reaction mixture was heated at 110° C. for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude material was dissolved in DMSO (1 mL), filtered and purified via reverse phase column chromatography using 10 to 99% MeOH—H2O (TFA modifier) to obtain ethyl 2-[5-amino-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]cyclopropanecarboxylate. 1H NMR (400.0 MHz, CDCl3) δ 8.23-8.15 (m, 3H), 7.59-7.50 (m, 3H), 4.19 (q, J=7.1 Hz, 2H), 2.64 (dd, J=6.2, 12.7 Hz, 1H), 2.25 (dd, J=5.5, 12.4 Hz, 1H), 1.66-1.61 (m, 2H) and 1.39-1.24 (m, 3H) ppm; LC/MS m/z 352.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl.[NH:19]([CH2:21][C:22](OC)=[O:23])[CH3:20]>CN(C)C=O>[CH3:20][N:19]1[C:8](=[O:10])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:22](=[O:23])[CH2:21]1
Reactant: CNCC(=O)OC
Reactant: Nc1cccnc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CC(=O)Nc2cccnc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 5.18 g (37.5 mmol) of 3-aminopicolinic acid in 100 ml of dimethylformamide is treated with 6.20 g (38.2 mmol) of N,N'-carbonyldiimidazole and the mixture is stirred at room temperature for 1 hour. To the light brown solution obtained there are added 3.84 g (38 mmol) of triethylamine and 5.30 g (38 mmol) of methyl sarcosinate hydrochloride and the mixture is stirred at the boiling point for 6 hours. After removing the dimethylformamide in vacuo, the residue is crystallized from ethanol. There is obtained 3,4-dihydro-4-methyl-2H-pyrido[3,2-e][1,4]diazepine-2,5(1H)-dione of melting point 272°-274°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:54][OH:55])[C@@H:21]([OH:53])[C@@H:22]([OH:52])[C@H:23]([OH:51])[C:24]([NH:26][C@H:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:28][C:29]([O:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:60](=[O:62])[CH3:61])(=O)C>N1C=CC=CC=1>[C:1]([O:51][C@@H:23]([C@H:22]([O:52][C:60](=[O:62])[CH3:61])[C@H:21]([O:53][C:24](=[O:25])[CH3:23])[C@@H:20]([NH:19][C:17](=[O:18])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:54][O:55][C:17](=[O:18])[CH3:12])[C:24]([NH:26][C@H:27]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:28][C:29]([O:31][CH:32]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:30])=[O:25])(=[O:8])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of diphenylmethyl (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (200 mg) in pyridine (5 ml) was added acetic anhydride (3 ml) and the mixture was stirred at room temperature for 4 days. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (100 ml) and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine respectively. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was passed through silica gel column chromatography, followed by elution with ethyl acetate-hexane (1:1). The effective fractions were combined and concentrated under reduced pressure to afford the title compound (85 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([C:23]([O:27][N:28]1N=NC2C=CC(=C[C:29]1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:23][O:27][N:28]([CH3:29])[C:17](=[O:19])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccncc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a mixture of Boc-β-(4-pyridyl)-L-alanine (75, 300 mg, 1.08 mmol) and NH(Me) OMe.HCl (1.2 eq., 1.30 mmol, 129 mg) in DCM (10 mL) was added HCTU (1.2 eq., 1.30 mmol, 536 mg) and DiPEA (3.5 eq., 3.78 mmol, 625 μL) and the mixture was stirred for 1 hour after which TLC analysis indicated complete conversion of starting material. The solvent was evaporated under reduced pressure en the residue was taken up in EtOAc, extracted with sat. aq. NaHCO3 (2×) and brine, dried over MgSO4 and concentrated in vacuo. The title compound was obtained after purification by column chromatography (EtOAc->2% MeOH/EtOAc) as a pale yellow solid (yield: 334 mg, 1.08 mmol, quant.). 1H NMR (400 MHz, CD3OD): δ=8.40 (d, J=4.59 Hz, 2H), 7.29 (d, J=4.88 Hz, 2H), 6.97 (d, J=7.26 Hz, 1H), 4.77-4.68 (m, 1H), 3.76 (s, 3H), 3.15 (s, 3H), 3.02 (dd, J=13.59, 4.85 Hz, 1H), 2.83-2.77 (m, 1H), 1.32 (s, 9H) ppm. 13C NMR (100 MHz, CD3OD): δ=173.49, 157.58, 149.88, 149.50, 126.48, 80.55, 62.25, 52.71, 38.03, 32.49, 28.66 ppm. [α]D23=−2.9 (c=1, MeOH). HRMS: calcd. for C15H43N3O4 [M+H]+310.17613. found 310.17615.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18](C3C(C(OCC)=O)=CC=CC=3)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH2:39][CH3:40])=[C:34]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:33]=1)(=O)C.[OH-].[Na+].O.[C:48]([OH:51])(=[O:50])C>C(O)C>[C:41]([C:34]1[CH:33]=[C:32]([C:10]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:48]([OH:51])=[O:50])=[CH:19][CH:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:37]=[CH:36][C:35]=1[NH:38][CH2:39][CH3:40])([CH3:44])([CH3:42])[CH3:43]
Reactant: CCNc1ccc(-c2cc(-c3ccc(-c4ccccc4C(=O)OCC)cc3)ccc2OCCCOC(C)=O)cc1C(C)(C)C
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCO)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
900 mg (1.74 mmol; 1 eq.) of ethyl 4′-(3-acetoxypropoxy)-3″-tert-butyl-4″-ethylamino-[1,1′;3′,1″]terphenyl-4-benzoate are dissolved in 10 ml of absolute ethanol. 312 mg (7.8 mmol; 4.5 eq.) of sodium hydroxide and 4 ml of H2O are added at room temperature and the mixture is then heated to reflux. These conditions are maintained for about 1 hour 30 minutes. The reaction medium is concentrated to a small volume; H2O is added to the precipitate formed, and the mixture is then acidified with acetic acid to pH ˜4-5. This suspension is fluidized by adding H2O and stirred at room temperature for 1 hour. The resulting mixture is filtered through a sinter funnel, rinsed with H2O until the filtrate is neutral, and oven-dried. 694 mg of 3″-tert-butyl-4″-ethylamino-4′-(3-hydroxypropoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid are thus obtained in the form of a white powder (yield=89%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl[CH2:16]CCl.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: O=C(O)c1ccc(Cl)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(Cl)c2ccccc12
Yield: 96 %

Procedure:
The synthesis method of Example 7-(1) was applied. The compound (1.93g) obtained in (2) above, 1,2-dichloroethane (50 ml), methanol (25 ml) and concentrated sulfuric acid (1.8 ml) were used as reagents to give 1.99 g of a red-brown solid (yield 96%).
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([OH:9])=O)[CH2:2][CH3:3].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>O1CCCC1>[CH:23]1([NH:26][C:7]([C@@H:5]2[C@@H:4]([CH2:1][CH2:2][CH3:3])[O:6]2)=[O:9])[CH2:25][CH2:24]1
Reactant: CCC[C@H]1O[C@@H]1C(=O)O
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC[C@H]1O[C@@H]1C(=O)NC1CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
(2S,3R)-3-Propyl-2-oxiranecarboxylic acid (118 mg, 0.8 mmol), triethylamine (0.8 mmol) and tetrahydrofuran (2 ml) were mixed, and the mixture was cooled to −20° C. A tetrahydrofuran solution (1 ml) of ethoxycarbonyl chloride (86 mg, 0.8 mmol) was gradually added, and the mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran solution (1 ml) of cyclopropylamine (48 mg, 0.8 mmol) was gradually added dropwise, and the mixture was stirred at the same temperature for 2 hours and at room temperature for 2 hours. After the reaction was quenched with water (10 ml), ethyl acetate (10 ml) was added and the solvent was evaporated away under reduced pressure. The mixture was extracted with ethyl acetate (10 ml), and washed with water (5 ml). The solvent was evaporated away under reduced pressure to obtain the title compound as a colorless oil (0.10 g, yield: 76%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)O1.Br[C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[N:26]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Reactant: Cc1ccnc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccnc(-c2ccc3c(c2)CCC3=O)n1

Procedure:
To a 25 mL flask containing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 50.0 mg, 0.19 mmol) was added 2-bromo-4-methyl pyrimidine (33.6 mg, 0.16 mmol) and sodium carbonate (23 mg, 0.76 mmol). The mixture was dissolved in 2 mL DME and 0.5 mL water. The mixture was purged with nitrogen for 15 minutes. Pd(dppf)Cl2 (2.9 mg, 5 mol %) was added and the solution was degassed for an additional 15 minutes. The reaction was heated under reflux for 16 hours. The reaction was concentrated to dryness and was partitioned between ethyl acetate and water. The water layer was extracted with ethyl acetate and the combined organic layers were washed twice with water and once with brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The final product was purified by silica chromatography on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) eluting with 0-50% ethyl acetate in heptanes. The product was obtained as a white solid (SM-1e, 8.7 mg, 20%). MS (ES+) 225.2 (M+H+). 1H NMR (CDCl3) δ 2.61 (s, 3H), 2.74-2.78 (m, 2H), 3.20 (t, 2H), 7.15 (d, 1H), 7.85 (d, 1H), 8.53 (d, 1H), 8.59 (s, 1H), 8.75 (d, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.N([O-])=O.[Na+].C(OCC)C.[F:21][B-](F)(F)F.[H+]>>[F:21][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1ccc2ncccc2c1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: CCOCC
Product: Fc1ccc2ncccc2c1
Reaction time: 1 h

Procedure:
To a solution of 6-aminoquinoline (1.0 g) in 42% tetrafluoroboric acid (5 ml), sodium nitrite (527 mg) was added under ice cooling and stirred at the same temperature for 1 hour. After addition of diethyl ether:ethyl acetate=1:1 (10 ml), the reaction mixture was decanted and the precipitate was dried. To the dried product, toluene (20 ml) was added and heated under reflux for 2 hours. The reaction mixture was decanted, and the resulting residue was dissolved in 1M aqueous hydrochloric acid and alkalized with saturated aqueous sodium carbonate. Insoluble materials were filtered off and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:diethyl ether=4:1 to 1:1) to give 6-fluoroquinoline (273 mg) as an orange-colored oil. To a solution of 6-fluoroquinoline thus obtained (273 mg) in methanol (50 ml), 10% palladium on activated carbon (50 mg) was added and stirred overnight under a hydrogen atmosphere (60 psi) at room temperature. After the reaction mixture was filtered, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 4:1) to give the titled compound, i.e., 6-fluoro-1,2,3,4-tetrahydroquinoline (172 mg) as a light-brown oil.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:36])([CH2:34]C)[CH2:6][C:7]1[N:8]=[C:9]([C:18](=[O:33])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[CH3:34][C:5]([CH3:4])([CH3:36])[CH2:6][C:7]1[N:8]=[C:9]([C:18]([OH:33])([CH3:1])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:16])[CH3:17])(=[O:14])=[O:13])[CH:11]=1
Reactant: C[Mg]Br
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2ccc(F)cn2)cc1
Temperature: 25 °C

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (6.1 mL, 18.42 mmol) was added to a −78° C. solution of 4-(2,2-dimethylbutyl)-2-{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (4.22 g, 9.21 mmol) in tetrahydrofuran (50 mL). After warming slowly to ambient temperature, the reaction was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]#[N:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2([C:14]#[N:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: BrCCCCCBr
Reactant: COc1ccc(CC#N)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C2(C#N)CCCCC2)cc1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A suspension of sodium hydride (0.3 g, 7.5 mmol, 60% dispersion in oil) in THF (9 mL) was cooled to 0° C. and treated slowly with 2-(3,4-dimethoxyphenyl)acetonitrile (0.532 g, 3 mmol) in THF (3 mL). After stirring for 15 min at this temperature 1,5-dibromopentane (0.49 mL, 3.6 mmol) in THF (3 mL) was added, the bath was removed, and the reaction was left stirring at room temperature for 18 h. The reaction was quenched with saturated aqueous ammonium chloride, extracted with EtOAc and washed with brine. The organic layer was dried (MgSO4), filtered and concentrated to provide 1-(3,4-dimethoxyphenyl)cyclohexanecarbonitrile, which was used without further purification in the next step. MS (ESI) m/z 246 (M+H)+.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[CH2:22]([OH:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1(C)C=CC=CC=1>[CH2:22]([O:30][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCO
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O

Procedure:
20 g (72.4 mmol) of 2-fluoro-naphthacene-5,12-dione, 94.3 g of 1-octanol, 30.01 g (217.2 mmol) of anhydrous potassium carbonate and 200 ml of dimethyl sulfoxide (DMSO) are stirred at a bath temperature of 100° C. for 20 hours. The reaction mixture is cooled, toluene/dilute hydrochloric acid are added and the organic phase is separated off, washed twice with water, dried with sodium sulfate and evaporated. The residue is washed with pentane and recrystallized from cyclohexane. Yield: 22.9 g (82%), melting point 127°-129° C.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)[C:10]([N:12]([C@H:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:23](O)=[O:24])[C@@H:13](C(OC)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[P].[F:52][C:53]([F:57])([F:56])[CH2:54][NH2:55]>CN(C)C=O>[CH2:41]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[C@H:9]1[NH:8][C:6](=[O:7])[C@@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:12]([C@H:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:23]([NH:55][CH2:54][C:53]([F:57])([F:56])[F:52])=[O:24])[C:10]1=[O:11]
Reactant: COC(=O)[C@@H](CC(C)C)N(C(=O)[C@H](NC(=O)OC(C)(C)C)C1Cc2ccccc2C1)[C@@H](C(=O)O)c1ccc(F)cc1
Reactant: NCC(F)(F)F
Agent: [P]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NCC(F)(F)F)c1ccc(F)cc1
Reaction time: 0.03 h

Procedure:
A solution of (2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid (73 mg) in N,N-dimethylformamide (2 ml) was sequentially treated with diisopropylethylamine (51 μL), phosphorus, (1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-(T-4)-hexafluorophosphate (80 mg) and then after 2 minutes, 2,2,2-trifluoroethylamine (25 μl). This reaction mixture was stirred for 2 hours before being partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before being dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in 4M hydrogen chloride in dioxane and stirred for 7 hours at room temperature. The reagent was removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic fraction was washed with brine before being dried over magnesium sulphate and evaporated in vacuo. The crude material was purified by column chromatography (silica) eluting with methanol: dichloromethane (1% to 3%) to furnish ((2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide (10 mg)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11][C:10]=1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:21]([CH:26]=O)[C:22]([O:24][CH3:25])=[O:23]>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:17][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][N:16]=2)=[CH:11][C:10]=1[C:18]#[N:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cl)C=O
Reactant: N#Cc1cc(C(N)=S)ccc1OCc1ccccc1
Solvent: CCCCO
Product: COC(=O)c1cnc(-c2ccc(OCc3ccccc3)c(C#N)c2)s1

Procedure:
4-(Benzyloxy)-3-cyanobenzenecarbothioamide and methyl 2-chloro-3-oxopropionate were heated under reflux in 1-butanol in the presence of Molecular Sieves 4A to obtain methyl 2-[4-(benzyloxy)-3-cyanophenyl]-1,3-thiazole-5-carboxylate. AP: 373(Na).