Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:47]=[CH:46][C:36]([O:37][C:38]3[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=3[C:40]#[N:41])=[CH:35][CH:34]=2)O1.COCCOC.O.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:47]=[CH:46][C:36]([O:37][C:38]4[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=4[C:40]#[N:41])=[CH:35][CH:34]=3)[C:10]=12
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3C#N)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5C#N)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 67.8 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.29 g, 5.19 mmol, 1 equiv), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzonitrile (2.0 g, 6.2 mmol, 1.2 equiv), tetrakis(triphenylphosphine)palladium (0.329 g, 0.311 mmol, 0.06 equiv), DME (21 mL), and sodium carbonate monohydrate (1.54 g, 12.5 mmol, 2.4 equiv) in water (16 mL) was heated at 85° C. for 60 h. Additional tetrakis(triphenylphosphine)palladium (0.100 g, 0.02 equiv) was added and the reaction mixture was heated at 85° C. for 6.5 h. The reaction mixture was allowed to cool to ambient temperature and was partitioned between saturated aqueous sodium bicarbonate solution (25 mL) and EtOAc (25 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was triturated from Et2O and purified by column chromatography on silica gel (elution with 1 L of 5% MeOH/CH2Cl2, 1 L of 10% MeOH/CH2Cl2, 1 L of 20% MeOH/CH2Cl2, and 1 L of 25% MeOH/CH2Cl2) to give cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile as a pale yellow solid (1.79 g, 3.52 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.24 (1H, s), 7.94 (1H, d, J=7.7 Hz), 7.68-7.73 (3H, m), 7.31-7.34 (3H, m), 7.18 (1H, d, J=8.5 Hz), 4.78-4.83 (1H, m), 2.21-2.51 (11H, m), 2.19 (3H, s), 2.05-2.08 (2H, m), 1.56-1.71 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.16 min. MS: MH+ 509.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10]>CN1CCCC1=O>[C:1]([O:4][CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10])(=[S:3])[CH3:2]
Reactant: FC(F)(F)CCBr
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=S)OCCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a suspension of 7.35 g of potassium thioacetate in 30 ml of N-methyl-2-pyrrolidone was added dropwise 11.39 g of 3-bromo-1,1,1-trifluoropropane over 15 minutes at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was heated to 80° C., followed by distillation under reduced pressure to obtain 9.99 g of 3,3,3-trifluoropropyl thioacetate represented by the formula:
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.Cl.[C:15]12([NH2:25])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.C(N(CC)CC)C.C>C(O)C.[OH-].[Na+]>[C:15]12([NH:25][C:2]3[NH:7][C:6]4[CH:8]=[C:9]([Cl:11])[S:10][C:5]=4[S:4](=[O:13])(=[O:12])[N:3]=3)[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S1(=O)N=C(NC23CC4CC(CC(C4)C2)C3)Nc2cc(Cl)sc21
Temperature: 120 °C
Reaction time: 41 h
Yield: 11 %

Procedure:
A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol), 1-adamantanamine hydrochloride (1.46 g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) was stirred for 41 h at 120° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (50 ml) followed by adjustment to pH <2 with 4M hydrochloric acid. The resulting dark mass was isolated by decantation and then partly dissolved in hot 1N sodium hydroxide (50 ml) followed by treatment with decolourising charcoal. After filtration, the solution was acidified to pH <2 and the precipitate was filtered off and recrystallised from ethanol to give 160 mg (11%) of the title compound as a beige solid; mp 339-340° C.; 1H-NMR (DMSO-d6): δ1.64 (br s, 6H), 2.02 (br s, 6H), 2.06 (br s, 3H), 6.67 (br s, 1H), 7.10 (s, 1H), 10.55 (br s, 1H); MS: m/e 371/373 (M+); (C15H18ClN3O2S2) calc C, 48.44; H, 4.88; N, 11.30; found C, 48.27; H, 4.85; N, 11.15.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C@@H:6]([CH2:23][CH3:24])[C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OCC1C=CC=CC=1)=[O:8])=[O:4].C1CC=CCC=1>C(O)C.[Pd]>[NH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[C:2]([F:26])([F:1])[F:25])[CH2:23][CH3:24]
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a heterogenous mixture of (S)-benzyl 2-(2-(2,2,2-trifluoroacetamido)butanamido)ethylcarbamate (1.1913 g, 3.20 mmol) and 10% Pd on carbon (1.2236 g) in ethanol (75 mL) was added 1,4-cyclohexadiene (3.0 mL, 32.0 mmol). The resulting mixture was stirred overnight at room temperature. The resulting mixture was then filtered through a bed of CELITE® and concentrated. The residue was dissolved in chloroform and filtered again through CELITE® to yield (S)—N-(2-aminoethyl)-2-(2,2,2-trifluoroacetamido)butanamide as an unstable oil which was stored in the freezer.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19]([NH:21][CH3:22])=[O:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=[CH:14][C:15]=1[CH:18]([S:17][CH3:16])[C:19]([NH:21][CH3:22])=[O:20]
Reactant: CNC(=O)CSC
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)C(SC)c1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70° C. and 17.9 g (0.15 mol) of 2-methylthio-N-methylacetamide in 20 ml of methylene chloride was added. To the (-70° C.) mixture was added dropwise a solution of 17.2 g (0.15 mole) of 95% t-butylhypochlorite in 30 ml of methylene chloride. The temperature was maintained at or below -65° C. for 1.5 hr, then 15.1 g (0.15 mole) of triethylamine was added rapidly. The solution was allowed to warm to room temperature and was washed with water. The organic solution was concentrated and the residue crystallized when mixed with isopropyl ether. The solid was recrystallized from isopropyl alcohol to give 31 g (65%) of yellow needles, m.p. 149.0°-150.0° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20](C(O)=O)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C.O>[Br:36][C:20]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=12
Reactant: O=C(O)c1c(-c2cccc(F)c2)nn2cc(C(F)(F)F)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(-c2nn3cc(C(F)(F)F)ccc3c2Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid (403 mg, 1.24 mmol) and NaHCO3 (355 mg, 3.4 eq) in DMF (10 ml) was added NBS (1.1 eq, 244 mg) and the resulting solution stirred at rt for 1.5 h. The mixture was diluted with water and extracted with ethyl acetate (3×10 ml). The combined organic phases were washed with water (3×10 ml), dried and concentrated in vacuo to give the title compound as a brown solid (390 mg, 85%). MH+ 358/359
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH2:10][CH:9]2[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C-:21]#[N:22].[K+]>O1CCCC1.O>[OH:13][CH:12]([CH:9]1[CH2:10][CH2:11][N:8]1[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:21]#[N:22]
Reactant: [C-]#N
Reactant: O=CC1CCN1C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)C1CCN1C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a solution of 1.4 g (5.57 mmoles) of 1-diphenylmethyl-2-formylazetidine in a mixture of 7.5 ml of tetrahydrofuran and 7.5 ml of water is added 0.91 ml (11.14 mmoles) of concentrated hydrochloric acid under cooling and then 0.724 g (11.14 mmoles) of potassium cyanide is added thereto. The mixture is stirred for 2 hours and extracted with 30 ml of ether. The aqueous layer is reextracted with 30 ml of ether. The extract and the above organic layer are combined, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 1.6 g of crude syrupy 2-hydroxy-2-(1-diphenylmethylazetidin-2-yl)acetonitrile in quantitative yield.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)[C:3]=1[CH:4]=[O:5]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(F)cccc1N1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Combine 2,6-difluorobenzaldehyde (5.00 g, 35.2 mmol), 1-benzylpiperazine (7.30 mL, 42.2 mmol) and potassium carbonate (5.83 g, 42.2 mmol) in dry N,N-dimethylformamide (10 mL) under an atmosphere of nitrogen. Heat the reaction to 80° C. for 4 hours. Cool the reaction to room temperature (20° C.) and stir overnight. Quench the reaction with water (100 mL) and extract with ethyl acetate (3×100 mL). Combine the organic extracts, wash with saturated ammonium chloride (4×100 mL), dry over anhydrous magnesium sulfate/sodium sulfate, filter and concentrate under vacuum to provide the crude product as a yellow oil. Purify the crude material by flash chromatography (ethyl acetate:hexane, 30:70, TLC Rf =0.40) followed by recrystallization from hot ethyl acetate (50 mL). Collect the crystals by suction filtration and rinse with hexane to yield 5.16 g. Concentrate the mother liquor and recrystallize the solid from ethyl acetate (15 mL). Isolate the crystals as above to yield 1.71 g. Repeat the above process to yield an additional 0.95 g. This provides the 2-fluoro-6-[4-benzylpiperazin-1-yl]-benzaldehyde (7.82 g) as yellow crystals, mp 94°-95° C.; 1H NMR (CDCl3) δ 10.26 (1H,-s), 7.44 (1H, td, J=8.1, 6.3 Hz). 7.34 (4H, m), 7.29 (1H, m), 6.84 (1H, d, J=8.3 Hz), 6.74 (1H, dd, J=8.3, 8.0 Hz), 3.59 (2H, s), 3.12 (4H, m), 2.66 (4H, m); 13C NMR (CDCl3) δ 187.63, 187.56, 165.73, 162.27, 155.82, 137.82, 135.62, 135.46, 129.20, 128.27, 127.18, 116.91, 116.82, 114.26, 114.22, 109.38, 109.09, 62.95, 53.51, 52.96; 19F NMR CDCl3) δ -115.94 (m); IR (KBr) 2825, 1690, 1607, 1462, 1005 cm-1 ; EI/MS (70eV) 298(80%), 91(100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31](S(C)=O)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31]([O:9][CH2:8][CH2:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: OCCc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCc2ccncc2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a solution of 4-pyridineethanol (0.862 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a yellow precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.231 g, 57%). Mass (m/z): 403.1 (M++1), 401.1 (M+−1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:30])[NH:17][S:18]([C:21]1[C:28]([CH3:29])=[CH:27][C:25]([CH3:26])=[CH:24][C:22]=1[CH3:23])(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:52]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:53]([C:58](ON1C(=O)CCC1=O)=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56].CN1CCOCC1.NCCN1CCNCC1>CN(C)C=O.[Pd]>[NH:52]([C:68]([O:70][C:71]([CH3:73])([CH3:72])[CH3:74])=[O:69])[C@H:53]([C:58]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:30])[NH:17][S:18]([C:21]1[C:28]([CH3:29])=[CH:27][C:25]([CH3:26])=[CH:24][C:22]=1[CH3:23])(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56]
Reactant: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)O)c(C)c1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: [Pd]
Agent: NCCN1CCNCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O)c(C)c1
Reaction time: 5 h
Yield: 90.1 %

Procedure:
In 120 ml of dimethylformamide are dissolved 9.5 g (13 millimoles) of Z-Gln-Arg(Mts)-Leu-OH obtained according to the process of Example 20 and 5.2 g (16 millimoles) of Boc-Leu-OSu, and 1.43 ml of N-methylmorpholine is added to the solution. Then 0.5 g of 10% Pd-C is added to the mixture, and the mixture is stirred for 5 hours in a current of H2. The N-(2-aminoethyl)piperazine is added to the mixture, the mixture is stirred for 1 hour. The 10% Pd-C is recovered by filtration, and the mixture is cancentrated under reduced pressure. The residue is added to a liquid mixture of 100 ml of ethyl acetate and 200 ml of a dilute aqueous solution of citric acid. The mixture is sufficiently stirred, and the ethyl acetate layer is recovered, washed with water, dried and concentrated under reduced pressure. Ether is added to the concentrate and the precipitate is recovered by filtration to obtain 9.5 g of intended Boc-Leu-Gln-Arg(Mts)-Leu-OH (the yield being 86.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1.[CH3:34][C:35]1[N:39]=[C:38]([NH2:40])[S:37][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:38]4[S:37][N:36]=[C:35]([CH3:34])[N:39]=4)(=[O:21])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Cc1nsc(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nsc(NS(=O)(=O)c2ccc3c(-c4ccc(Cl)cc4C)nccc3c2)n1
Reaction time: 2 h
Yield: 75 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-(4-chloro-2-methylphenyl)isoquinoline-6-sulfonate (Intermediate DDDDD; 59.9 mg, 0.120 mmol), 3-methyl-1,2,4-thiadiazol-5-amine (27.6 mg, 0.240 mmol), cesium carbonate (117 mg, 0.360 mmol), and DMF (0.6 mL). The vial was sonicated for 20 s, and the mixture was stirred further for 2 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim 15-micron column, 0-5% MeOH/DCM) to give 1-(4-chloro-2-methylphenyl)-N-(3-methyl-1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (38.94 mg, 0.090 mmol, 75% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.16 (d, J=5.8 Hz, 1H), 7.89 (dd, J=1.9, 8.9 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.44-7.39 (m, 1H), 7.33 (d, J=8.1 Hz, 1H), 2.27 (s, 3H), 1.97 (s, 3H). m/z (ESI) 431.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:15][CH2:16]Cl)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:2][N:3]([CH2:15][CH2:16][S:27][C:24]1[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CN(CCCl)CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCSc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Yield: 92.7 %

Procedure:
2-[N-Methyl-N-(4-nitrophenethyl)amino]ethyl chloride hydrochloride (3.0 g), 4-nitrothiophenol (1.7 g) and potassium carbonate (4.0 g) in acetonitrile (100 ml) were stirred at reflux for 16 hours. After evaporation, the residue was partitioned between water and ethyl acetate. The organic liquors were washed with saturated aqueous brine, dried (MgSO4), filtered and evaporated to give an orange oil (3.6 g). Chromatography on silica ("Kieselgel 60"-Trade Mark) eluting with ethyl acetate followed by collection of suitable fractions gave on evaporation the title compound as a yellow solid, (3.05 g), m.p. 56°-7°.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N12CCN(CC1)CC2.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(OCC)(=O)C>[CH:1]1([O:7][S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 90.4 %

Procedure:
5.0 g (0.05 mol) cyclohexanol and 11.2 g (0.1 mol) 1,4-diazabicyclo[2.2.2]octane are added to 50 mL ethyl acetate. This solution is cooled in an ice bath and 14.3 g (0.075 mol) tosyl chloride in 30 ml ethyl acetate is added drop-wise over 15 minutes. The ice bath is removed and the mixture is allowed to stir at room temperature for 4 days. After this time the solid precipitate is filtered and washed. The ethyl acetate filtrate and washings are then combined and washed successively with 10% HCl, saturated aq NaHCO3 and brine. The ethyl acetate is then evaporated and the resulting oil is purified by column chromatography to yield 11.5 g (90%) of cyclohexyl-p-toluenesulfonate.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[SH:11][CH2:12][C:13]([NH2:15])=[O:14].C[O-].[Na+]>CN(C=O)C.CO>[NH2:6][C:5]1[C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[C:3]=2[S:11][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)CS
Reactant: N#Cc1cccc(Br)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(Br)cccc2c1N
Temperature: 70 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a stirred solution of 3-bromo-2-fluoro-benzonitrile (2 g, 10 mmol) in DMF (50 mL) was added 2-mercaptoacetamide (1.2 eq., 12 mL, 100 mg/mL in MeOH-ammonia solution) followed by sodium methoxide (1.2 eq., 24 mL, 0.5 M in MeOH) at room temperature under nitrogen. After 2 h, the resulting homogenous yellow solution was warmed to 70° C. for 17 h. Upon cooling to room temperature, the resulting dark green reaction mixture was concentrated to give a green solid. This solid was diluted with MeOH and collected via filtration to give 2.0 g (74%) of 3-amino-7-bromo-benzo[b]thiophene-2-carboxylic acid amide.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:8][C@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:17])[CH3:16]
Reactant: O[C@@H](CC1CCCC1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CC1CCCC1)c1ccccc1
Reaction time: 6 h
Yield: 100 %

Procedure:
A solution of 406 mg (2.13 mmol) of (S)-2-cyclopentyl-1-phenylethanol (from Step C) in 9 mL of pyridine was treated with 1 mL of acetic anhydride. After stirring for 6 h, the reaction was concentrated. Flash chromatography on silica gel using 93:7 v/v hexanes/EtOAc afforded 495 mg (100%) of the title compound: RF: 0.75 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz): δ 1.10-1.21 (m, 2H), 1.44-2.04 (m, 9H), 2.05 (s, 3H), 5.75 (dd, J=8.0, 6.1, 1H), 7.25-7.34 (m, 5H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH:40]([CH3:43])[CH2:41][OH:42]>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH:40]([CH3:43])[CH2:41][OH:42])=[O:34])[C:15]1=[O:38]
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Solvent: CCO
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 2-amino-1-propanol (0.0041 mL, 0.051 mmol) for 10 min. (150° C. in a microwave vessel. An additional 0.001 mL of the amine was added to the reaction and it was further microwaved for 20 min.@150° C. The reaction was then cooled to ambient temperature and the resulting suspension was filtered, washed with EtOH and then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97 (d, J=6.59 Hz, 3 H), 3.25-3.31 (m, 2 H), 3.86-3.95 (m, 3 H), 4.11 (s, 2 H), 4.43-4.52 (m, 1 H), 4.57-4.65 (m, 1 H), 4.90 (t, J=5.31 Hz, 1 H), 7.10-7.16 (m, 2 H), 7.31-7.38 (m, 2 H), 7.80-7.85 (m, 4 H), 8.15-8.18 (m, 1 H), 8.52 (d, J=1.46 Hz, 1 H), 9.96 (d, J=7.87 Hz, 1 H), 17.25 (s, 1 H); ES+ MS: 545 (M+H+).