Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11](=[O:13])[NH2:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:14]([O:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20])[CH3:15]>>[C:4]([C:3]1[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[O:16][CH2:14][CH3:15])=[C:10]([CH:9]=[CH:8][CH:7]=1)[C:11]([NH2:12])=[O:13])(=[O:5])[NH2:6]
Reactant: NC(=O)c1cccc(C(N)=O)c1N
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCOc1ccccc1C(=O)Nc1c(C(N)=O)cccc1C(N)=O

Procedure:
The title compound was prepared from 2-amino-3-carbamoylbenzamide and 2-ethoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as colorless crystals (33%), m.p. 224°-225° C. Found: C,62.57; H,5.18; N,12.81. C17H17N3O4 requires C,62.37; H,5.24; N,12.84%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1.[CH3:40][O:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](O)=[O:45].C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44]([NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)=[O:45]
Reactant: COc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(=O)NCC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HATU (293 mg, 0.77 mmol) was added to a DMF (3 mL) solution of the compound (150 mg, 0.7 mmol) synthesized in (2), 2-methoxybenzoic acid (117 mg, 0.77 mmol), and diisopropylethylamine (0.27 mL, 1.54 mmol), and the mixture was stirred at room temperature for 24 hours. After adding ethyl acetate, the reaction mixture was washed twice with distilled water, and once with saturated brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (244 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 72.8 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-5-(trifluoromethyl)pyridine (138 mg, 0.76 mmol), DIEA (0.27 ml, 1.52 mmol) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (112 mg), a white solid, in 73% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(O)(O)(=O)=O.Cl[C:22]1[NH:23][CH2:24][CH2:25][N:26]=1>C(#N)C.ClCCl>[CH3:1][O:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:22]3[NH:26][CH2:25][CH2:24][N:23]=3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2ccc(N)cc2)s1
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(Cc2ccc(NC3=NCCN3)cc2)s1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
To a solution of [4-(5-methoxythien-2-ylmethyl)-phenylamine (145 mg, 0.66 mmol) in acetonitrile (10 ml) was added 2-chloro-2-imidazoline sulfate (155 mg, 0.76 mmol) at 20–25° C. under nitrogen. The resulting suspension was heated at 80° C. for 1.5 hours. The mixture was diluted with dichloromethane and washed with 10% sodium hydroxide, water, dried (Na2SO4), and concentrated to dryness. Purification by preparative TLC, eluting with ethyl acetate/methyl alcohol/isopropylamine, gave 2-[4-(5-methoxythien-2-ylmethyl)phenyl]amino-imidazoline (132 mg, 70%) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.12 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.39 (dt, J=3.7, 1.1 Hz, 1H), 5.98 (d, J=3.7 Hz, 1H), 3.92 (bs, 2H), 3.82 (S, 3H), 3.52 (S, 4H), 3.15–3.35 (broad, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH3:32][C:33]1[S:37][C:36]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[N:35][C:34]=1/[CH:44]=[CH:45]/[C:46]1[C:47]([OH:57])=[N:48][N:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:50]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:5]1[CH:4]=[C:3]([CH2:2][O:57][C:47]2[C:46](/[CH:45]=[CH:44]/[C:34]3[N:35]=[C:36]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[S:37][C:33]=3[CH3:32])=[CH:50][N:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:48]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: Cc1sc(N2CCCCC2)nc1/C=C/c1cn(-c2ccccc2)nc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCCCC5)sc4C)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.66 g), 4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-ol hydrochloride (0.44 g), potassium carbonate (0.30 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl [4-{4-[(2-methoxy-4-{[(4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl]acetate (0.59 g, yield 72%) as crystals. Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 131-132° C.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH2:21].Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24].CN1CCOCC1>C(Cl)Cl>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:5][CH2:4][CH:3]1[CH2:20][NH:21][C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CC(C)COC(=O)Cl
Reactant: CN1c2ccccc2C(c2ccccc2F)=NCC1CN
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)COC(=O)NCC1CN=C(c2ccccc2F)c2ccccc2N1C
Temperature: 25 °C
Yield: 68.2 %

Procedure:
According to the method of Example 1, 1-methyl-2-aminomethyl-5-(2'-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (250 mg, 0.88 mmole) and isobutyl chloroformate (114 μl, 0.88 mmole) were combined with 4 ml of dry methylene chloride, and 97 μl of N-methylmorpholine (0.88 mmole) at -5° C. was added to the mixture. The resulting reaction mixture was allowed to warm to room temperature over 2 hours, and after dilution and washing, rotoevaporation of the dried extracts of the reaction afforded 230 mg of an oil which was purified by silica gel chromatography (ethyl acetate-hexane elution, 7:3 v/v) to give the analytical sample (120 mg) which was 98% pure by HPLC.
Reaction SMILES: [CH3:1]C([O-])(C)C.[Na+].[CH:7]1[CH:8]=[C:9]2[C:17](=[O:18])[N:16]([CH:19]3[C:25](=[O:26])[NH:24][C:22](=[O:23])[CH2:21][CH2:20]3)[C:14](=[O:15])[C:10]2=[C:11]([NH2:13])[CH:12]=1.CI.C(O)(=O)C>CS(C)=O>[NH2:13][C:11]1[CH:12]=[CH:7][CH:8]=[C:9]2[C:10]=1[C:14](=[O:15])[N:16]([CH:19]1[CH2:20][CH2:21][C:22](=[O:23])[N:24]([CH3:1])[C:25]1=[O:26])[C:17]2=[O:18]
Reactant: CC(C)(C)[O-]
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CI
Solvent: CS(C)=O
Product: CN1C(=O)CCC(N2C(=O)c3cccc(N)c3C2=O)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
To a solution of NaOtBu (0.074 g, 0.769 mmol) in DMSO (0.8 mL) was added a solution of pomalidomide (0.100 g, 0.366 mmol) in DMSO (0.5 mL plus 0.5 mL rinse) dropwise. The reaction was stirred for 10 min at room temperature followed by the addition of methyl iodide (0.025 mL, 0.403 mmol). After 18 h, glacial acetic acid (0.1 mL) was added to the reaction volatiles were removed in vacuo, and the crude dark-brown residue was purified by preparative reverse phase HPLC to afford 29 (0.02 g, 19%) as light yellow powder. 1H NMR (400 MHz, DMSO) δ 7.46 (dd, J=8.4, 7.0 Hz, 1H), 7.00 (dd, J=7.6, 5.6 Hz, 2H), 6.53 (br s, 2H), 5.11 (dd, J=13.2, 5.7 Hz, 1H), 2.97-2.83 (m, 1H), 2.76 (s, 1H), 2.57-2.51 (m, 1H), 2.06-1.91 (m, 1H). MS (ESI) m/z calcd for C14H14N3O4[M+H]+ 288.3, found: 288.5.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (434 mg, 87%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=1.[C:18]1([C:24]2[O:25][C:26]([C:32]([F:35])([F:34])[F:33])=[C:27]([C:29](O)=[O:30])[N:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[N:10]=[CH:11][C:12]([NH:15][C:29]([C:27]2[N:28]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:25][C:26]=2[C:32]([F:34])([F:35])[F:33])=[O:30])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(NC2CC3CCC2C3)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(NC2CC3CCC2C3)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Yield: 17 %

Procedure:
Bicyclo[2.2.1]hept-2-yl-(5-nitro-pyridin-2-yl)-amine (102 mg, 0.4 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (123 mg, 0.48 mmol), Et3N (281 uL, 2 mmol) and BOP (194 mg. 0.444 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(bicyclo[2.2.1]hept-2-ylamino)-pyridin-3-yl]-amide as a light purple solid (30 mg). ES-MS calcd for C23H21F3N4O2 (m/e) 442.44, obsd 443.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:3])[CH3:2].[CH2:20](Br)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Na+]>O1CCCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]=1[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CC(=O)c1c(-c2ccc(Cl)cc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccc(Cl)cc2)n(CCc2ccccc2)c2ccccc12
Reaction time: 6 h
Yield: 46 %

Procedure:
A solution of 3-acetyl-2-(4-chlorophenyl)indole (53.9 mg, 0.2 mmol) and phenethylbromide (30 μL, 0.22 mmol) in tetrahydrofuran is treated with NaH (60% dispersion in mineral oil, 24 mg, 0.6 mmol) at room temperature, shaken for 6 h, quenched with saturated NaHCO3 and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford the title product, 34 mg (46% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Na].[CH3:14][OH:15]>>[CH3:14][O:15][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: CO
Agent: [Na]
Product: COC(=O)c1cc(C)nc(OC)n1

Procedure:
30.0 g of methyl 2-chloro-6-methylpyrimidine-4-carboxylate are added to a solution of 4.2 g of sodium in 100 ml of methanol. The mixture is heated under reflux for 2 h and concentrated under reduced pressure, and the residue is taken upon in dichloromethane/water. The organic phase is separated off and the aqueous solution is extracted a further five times using dichloromethane. The combined organic extracts are dried over sodium sulfate and the solvent is distilled off under reduced pressure. 25.5 g of methyl 2-methoxy-6-methylpyrimidine-4-carboxylate of melting point 101°-103° C. are obtained in this way.
Reaction SMILES: O[B:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[O:3]1.C[C@@:17]1([OH:27])[C@H:22]([OH:23])[CH2:21][C@@H:20]2[CH2:24][C@H:18]1[C:19]2([CH3:26])[CH3:25].[CH2:28]1COCC1>>[OH:3][CH:4]([CH2:5][CH2:6][CH2:7][B:2]1[O:23][C@:22]2([CH3:28])[C@@H:17]([C@@H:18]3[CH2:24][C@H:20]([CH2:21]2)[C:19]3([CH3:25])[CH3:26])[O:27]1)[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)CC1CCCB(O)O1
Reactant: CC1(C)[C@@H]2C[C@@H](O)[C@@](C)(O)[C@H]1C2
Reactant: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)CCCB1O[C@@H]2[C@@H]3C[C@H](C[C@]2(C)O1)C3(C)C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a solution of tert-butyl 2-(2-hydroxy-1,2-oxaborinan-6-yl)acetate XLVIII (641 mg, 3.00 mmol) in THF (20 mL) was added (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (509 mg, 3 mol) at room temperature. The reaction mixture was stirred for 16 h and concentrated under vacuum. The residue was purified by column chromatography (100% hexane→40% EtOAc/hexane) on silica gel to give tert-butyl 3-hydroxy-6-[(1R,2R,6S,8R)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]hexanoate XLIX (790 mg, 2.16 mmol, 71.9% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23]>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:25][CH2:21][CH:22]([CH3:24])[CH3:23])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: CC(C)CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCC(C)C)c1C
Yield: 55.3 %

Procedure:
A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (40.0 g, 181 mmol), triethylamine (26.5 mL, 190 mmol), and isobutyl amine (18.9 mL, 190 mmol) in N,N-dimethylformamide (500 mL) was stirred at room temperature over night. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL) and washed with water (3×80 mL) and brine (40 mL). The aqueous was extracted with ethyl acetate (3×50 mL) and the back-extracts washed with water (3×40 mL) and brine (30 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by HPFC eluting with a gradient of 10-30% ethyl acetate in hexanes to give 25.8 g of 2-chloro-N-isobutyl-5,6-dimethyl-3-nitropyridin-4-amine as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25]Cl)[CH2:2][CH2:3][CH3:4].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH3:18])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]=1[CH2:25][N:31]1[C:27](=[O:37])[C:28]2[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30]1=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2ccc(OCC)cc12
Yield: 97.8 %

Procedure:
A solution of 4-butoxy-6-ethoxy-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (0.38 g, 1 mmol) and potassium phthalimide (0.28 g, 1.5 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{(4-butoxy-6-ethoxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (0.48 g, 98.0%) as an amorphous.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][NH:9][CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].O>C(Cl)Cl>[C:14]([O:13][C:12]([NH:11][C@@H:7]([CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:8][N:9]([CH3:10])[C:26](=[O:27])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNC[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C[C@H](CC1CCCC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 40 %

Procedure:
To a mixture of tert-butyl (S)-3-cyclopentyl-1-(methylamino)propan-2-ylcarbamate (900 mg, 3.52 mmol) and Et3N (1.5 mL, 10.6 mmol) in CH2Cl2 (10 mL) was added dropwise a solution of CbzCl (720 mg, 4.22 mmol) in CH2Cl2 (5 mL) at 0° C. After stirring for an additional 2 h, water (30 mL) was added and the mixture was extracted with CH2Cl2 (2×10 mL). The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica chromatography to obtain benzyl (S)-2-(t-butoxycarbonylamino)-3-cyclopentylpropylmethylcarbamate (550 mg, 40%) as an oil. 1H NMR (CDCl3, 400 MHz) δ 1.10 (m, 2H), 1.43 (s, 9H), 1.49 (m, 3H), 1.60 (m, 3H), 1.81 (m, 3H), 2.96 (s, 3H), 3.15 (m, 1H), 3.40 (m, 1H), 3.83 (brs, 1H), 4.57 (brs, 1H), 5.16 (s, 2H), 7.33 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12].ClCC(C1C=CC=CC=1)=O.[NH2:27][C:28]1[N:29]=[CH:30][NH:31][C:32]=1[C:33]#[N:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]2[CH:30]=[N:31][C:32]([C:33]#[N:34])=[C:28]2[N:27]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1Cl
Agent: O=C(CCl)c1ccccc1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccccc3Cl)nc12
Yield: 17 %

Procedure:
Reaction of 1-(2-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 2-chloro-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (55 mg, 17%). MS (ISP) 323.1 [(M+H)+]; mp 180° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[CH:17]1([O:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOC2CCCCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C1CCC(OCCC2CCNCC2)CC1
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(cyclohexyloxy)ethyl]piperidine (182 mg, 0.59 mmol) in MeOH (2 mL) was added 2N anhydrous HCl/ether (0.75 mL, 1.5 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, the product (38.0 mg, 30%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 3.46-3.29 (m, 2H), 3.16 (1, 2H), 3.02 (m, 2H), 2.56 (m, 2H), 2.17 (br, 1H), 1.88 (m, 2H), 1.71-1.64 (m, 4H), 1.52-1.42 (m, 4H), 1.25-1.22 (m, 3H), 1.99-1.13 (m, 2H), 1.11-1.08 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 64.8, 46.3, 37.0, 33.2, 32.8, 32.0, 27.2, 25.4, 23.9.
Reaction SMILES: [Li+].[OH-].N(C1C=C(C=CC=1)C([NH:12][CH2:13][C:14]([NH:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=O)C(N)=N.FC(F)(F)C(O)=O>O>[NH2:12][CH2:13][C:14]([NH:16][CH:17]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=N)N)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(NC(=O)CN)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiOH x H2O (775 mg) was added to a solution of ethyl 3-{2-[(3-(guanidino)benzoyl)amino]acetamido}-3-phenyl-propanoate from II.1-E (2.0 g) in 100 ml of water and the mixture was stirred at room temperature for 1 h. It was then neutralized with trifluoroacetic acid and concentrated. After purification by HPLC, a white solid was obtained (yield: 1.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.[CH3:15][S:16][CH2:17][C:18](=O)[CH3:19].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[NH:4][C:18]([CH3:19])=[C:17]2[S:16][CH3:15]
Reactant: Nc1ccccc1Cl
Reactant: CSCC(C)=O
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CSc1c(C)[nH]c2c(Cl)cccc12
Temperature: -65 °C
Reaction time: 1 h

Procedure:
Using the procedure described in J. Amer. Chem. Soc., 1974, 96 (17) 5495 , 2-chloroaniline (1.27 g, 10 mmole) was dissolved in dichloromethane (35 ml) and cooled to −65° C. To this solution was added dropwise with vigorous stirring, t-butyl hypochlorite (1.08 g, 10 mmole) in dichloromethane (5 ml). After 10 minutes 1-methylsulfanyl-propan-2-one (1.04 g, 10 mmole) dissolved in dichloromethane (5 ml) was added. The mixture was stirred at −65° C. for 1 h more. At this point triethylamine (1.01 g, 10 mmole) dissolved in dichloromethane (5 ml) was added. Upon completion of the addition, the reaction mixture was allowed to reach ambient temperature. Water was added and the layers were separated, the organic layer was dried over magnesium sulfate, filtered and the solvent evaporated to dryness. The residue was purified by column chromatography on silica gel using a mixture of hexane-ethyl acetate (95:5) to elute 7-chloro-2-methyl-3-methylsulfanyl-1H-indole (1.94 g) as an oil.