Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:48])[CH2:10][CH2:11][C:12]([O:14][C:15]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:40][C@H:39]([CH2:41][NH:42][C:43](=[O:45])[CH3:44])[O:38][C:37]3=[O:46])=[CH:32][C:31]=2[F:47])[CH2:20][CH2:19][N:18](OC(C)(C)C)[C:17](=C=O)[CH2:16]1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9](=[O:48])[CH2:10][CH2:11][C:12]([O:14][C:15]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:40][C@H:39]([CH2:41][NH:42][C:43](=[O:45])[CH3:44])[O:38][C:37]3=[O:46])=[CH:32][C:31]=2[F:47])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCN(OC(C)(C)C)C(=C=O)C3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCNCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
820 mg of succinic acid 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-1-tert-butoxy-carbonyl-piperidin-4-yl ester benzyl ester (MW: 671.72, 1.23 mmol) were dissolved in 4 ml of trifluoro acetic acid. The reaction mixture was stirred at room temperature for one hour. The solvent was evaporated, the residue dissolved in 30 ml of a 9/1 dichloromethane/methanol mixture and the organic layer washed successively with 30 ml of a saturated aqueous sodium bicarbonate solution and 30 ml of brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue was purified by chromatography over silica, using a 95/5 dichloromethane/methanol mixture with 2% triethylamine as eluent. Yield: 420 mg, 60%. MS: 572.7 (M+H)+, Method ESI+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH3:47][C@H:48](Cl)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C@@H:48]([CH3:47])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC[C@H](C)Cl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 83 %

Procedure:
Putting 4-benzyloxyphenol (5 g) and triphenyl phosphine (23.58 g) into a two-neck bottle (500 mL), and then vacuuming for 1 hour. Under the protection of nitrogen, adding dichloromethane (150 mL) followed by stirring to dissolve. Adding diethyl azodicarboxylate (22.73 g) into the bottle on ice bath followed by stirring. Adding (s)-2-octylchloride (13.36 g), reacting 24 hours under room temperature. Extracting by water and dichloromethane, drying with anhydrous magnesium sulfate, removing the solvent by a rotary vacuum evaporator, column chromatography of the crude product is carried out to gain a pure target compound (19.41 g). The yield is about 83%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1>O1CCCC1.CN(C)C=O.CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[C:18]([NH:17][C:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[O:10])[CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: Cc1cccnc1C(=O)O
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
To a solution of 3-methylpyridine-2-carboxylic acid (1.38 g, 10.1 mmol) in tetrahydrofuran (100 mL) were added N,N-dimethylformamide (2 drops) and oxalyl chloride (1.75 mL, 20.2 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (50 mL). A solution of 5-(3-aminophenoxy)pyridin-2-amine (1.83 g, 9.09 mmol) in N,N-dimethylacetamide (5 mL) was added with stirring at room temperature, and the mixture was stirred at room temperature for 13 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure and washed with ethyl acetate-hexane to give the title compound (1.84 g, 57%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:15](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:13]#[N:14])[C:11]=1[O:12][CH3:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(O)c(C#N)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(Cl)c(OC)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
Methyl 3-chloro-5-cyano-4-hydroxybenzoate (1.27 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (5.00 g) and dimethylsulfuric acid (1.70 mL) were added to the solution, and then the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.03 g) as a colorless crystal.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH:10]([OH:22])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.FC(F)(F)C([O-])=O.C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[OH:22])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: OC1CNCCC1(O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product of step 2 (500 mg, 1.37 mmol) was dissolved in methylene chloride (10 mL) and the resulting solution cooled to 0° C. Trifluoroacetic acid (3 mL) was slowly added and the reaction was allowed to stir at 0° C. for 2 h, before concentration under reduced pressure. The trifluoroacetate salt was dissolved in tetrahydrofuran and excess triethylamine was added. Solids generated were removed by suction filtration and the supernatant solution was concentrated to afford 4-(4-chloro-phenyl)-piperidine-3,4-diol.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][CH:8]=[C:9]3[C:18]([N:17]=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[C:15]4[C:19](O)=[O:20])=[N:10]3)=[C:5]2[CH:4]=[N:3]1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:15]1[C:16]2[C:11](=[N:10][C:9]3[C:18]([N:17]=2)=[C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]2=[CH:7][CH:8]=3)[CH:12]=[CH:13][CH:14]=1)=[O:20]
Reactant: Cn1ncc2c3nc4c(C(=O)O)cccc4nc3ccc21
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(cnn4C)c3nc12

Procedure:
3-Methyl-3H-Pyrazolo[4,3-α]phenazine-10-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 3-methyl-3H-Pyrazolo[4,3-α]phenazine-10-carboxylic acid (II.10) and N,N-dimethylethylenediamine
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[F:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][NH:19][C:20]([C:22]2[S:26][C:25]([N:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]3=[O:34])=[N:24][C:23]=2[CH3:35])=[O:21])=[CH:16][CH:15]=1>>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:33][C:30]2[CH:31]=[CH:32][N:27]([C:25]3[S:26][C:22]([C:20]([NH:19][CH2:18][C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:37][CH:36]=4)=[O:21])=[C:23]([CH3:35])[N:24]=3)[C:28](=[O:34])[CH:29]=2)=[CH:6][CH:5]=1
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Product: Cc1nc(-n2ccc(OCc3ccc(OC(F)F)cc3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 25 %

Procedure:
Following the procedure as described in Example 9, making variation only as required to use 4-(difluoromethoxy)benzyl bromide in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-(4-fluorobenzyl)-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 25% yield: mp 242-244° C. (dichloromethane/methanol); 1H NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.8 Hz, 1H), 8.60 (dd, J=8.1, 3.0 Hz, 1H), 7.56-7.47 (m, 2H), 7.34-7.08 (m, 7H), 6.43-6.32 (m, 1H), 6.22 (s, 1H), 5.15 (s, 2H), 4.34 (d, J=5.8 Hz, 2H), 2.52 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 163.2, 161.9, 160.0, 151.4, 150.4, 136.1, 133.7, 132.7, 130.5, 129.8, 123.6, 120.1, 119.2, 116.7, 115.6, 113.3, 104.3, 97.5, 70.1, 44.6, 17.5; MS (ES+) m/z 516.4 (M+1).
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.[CH2:12]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.O>O1CCCC1>[CH2:12]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:9][N:8]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([Br:2])=[CH:4][CH:5]=3)[CH:25]=2)=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ON=Cc1ccc(Br)cc1
Reactant: C#Cc1ccc(OCCCCC)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(Br)cc3)no2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of 4-bromobenzaldehyde oxime chloride (647 mg) and 4-n-pentyloxy-phenylacetylene (650 mg) in tetrahydrofuran (7 ml) was added triethylamine (0.5 ml) in tetrahydrofuran (5 ml) dropwise at 40° C. The solution was stirred at 40° C. for 30 minutes, poured into water and extracted with ethyl acetate. The organic layer was washed with H2O, brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with acetonitrile. The precipitate was collected by filtration and dried to give 4-[5-(4-n-pentyloxyphenyl)isoxazol-3-yl]bromobenzene (0.59 g).
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[C:10]([O:14][C:15]([O:17][C:18]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[C:27]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([CH2:49][C:50]([O:52][CH3:53])=[O:51])=[CH:45][C:44]=3[CH:54]=O)=[CH:39][CH:38]=2)[C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)C.C(OCC)(=O)C>[C:10]([O:14][C:15]([O:17][C:18]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[C:27]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([CH2:49][C:50]([O:52][CH3:53])=[O:51])=[CH:45][C:44]=3[CH:54]=[N:8][OH:9])=[CH:39][CH:38]=2)[C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: NO
Reactant: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C=NO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
Pyridine (49 μl, 0.62 mmol) and hydroxylamine hydrochloride (42 mg, 0.62 mmol) were added to a solution of tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({2′-formyl-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (198 mg, 0.307 mmol) obtained in Example (45-2) in ethanol (4 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was subjected to silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=2/1) to give crude tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({2′-[(hydroxyimino)methyl]-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (170 mg).
Reaction SMILES: C([NH:11][C:12](=[N:45]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:34]([NH:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.[ClH:56]>[Pd].CC(O)=O>[ClH:56].[C:21]1([CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]([NH:18][C@H:17]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:45])=[O:33])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H](NC(=O)[C@H](CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
Prepared according to the method described in Example 1(g) above from (R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(S)-N-(1-phenylethyl)arginine amide (0.6 g; 0.8 mmol; from step (d) above), 10% Pd/C (w/w; 200 mg), HOAc (25 mL), overnight reaction time. The crude acetate salt was converted to the hydrochloride to give 0.4 g (99%) of the title compound as a solid.
Reaction SMILES: CON(C)[C:4](=[O:18])[CH:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]([CH3:9])([CH3:8])[CH3:7].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:4](=[O:18])[CH:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:6]([CH3:7])([CH3:8])[CH3:9])=[CH:23][CH:22]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(Cl)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
tert-Butyl 1-(methoxy(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (Example 1, 466 mg, 1.70 mmol) was dissolved in dry THF (10 mL). (4-Chlorophenyl)magnesium bromide (CAS 873-77-8, 1.0 M in THF, 6.79 mL, 6.79 mmol) was then added dropwise at rt. After stirring at rt overnight the reaction was quenched with NH4Cl and extracted with EtOAc (2×50 mL). The combined organic phases were washed once with water, dried over MgSO4 and filtered. After removal of the solvent the product was purified on a silica gel column eluted with heptane:EtOAc 10-20% to give tert-butyl 1-(4-chlorophenyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (137 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][C:12]([CH3:17])([CH3:16])[CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:18].[C:19]([NH:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:31][C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:24]([NH:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:33])[C:12]([CH3:16])([CH3:17])[CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:18]
Reactant: CC1(C)CN(C(=O)c2ccc(N)c(F)c2)CCN1
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2(C)C)c1
Yield: 39.2 %

Procedure:
To (4-amino-3-fluorophenyl)(3,3-dimethylpiperazin-1-yl)methanone (0.521 mmol, 131 mg) in acetonitrile (5.213 mL) was added N-tert-butyl-3-(chloromethyl)benzamide (0.573 mmol, 129 mg), and triethylamine (1.040 mmol, 145 μl, 105 mg). A catalytic amount of sodium iodide was added. The mixture was heated to reflux for 3 hours. The mixture was allowed to cool and ethyl acetate was added. The organic mixture was washed with water, dried with sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica chromatography (eluting with 5% methanol in dichloromethane) to yield the title compound (90 mg). MS (ESI) m/z 441.4 [M+H]+
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Na].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[C:11]([F:18])[CH:10]=1>CO>[OH:3][N:2]=[C:16]([NH2:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=1[F:18]
Reactant: N#CCc1ccc(Br)cc1F
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(Cc1ccc(Br)cc1F)=NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
Hydroxylamine hydrochloride (8.93 g, 128.5 mmol), was added in one portion to a solution of sodium methoxide, freshly prepared from sodium (2.96 g, 128.5 mmol) in methanol (200 mL). The resulting mixture was stirred 1 hour at room temperature, during which a precipitate was formed. 4-Bromo-2-fluorophenylacetonitrile (11.0 g, 51.4 mmol) was added and the resulting mixture heated to reflux for 20 hours. A white solid was removed by filtration of the hot mixture and discarded. The filtrate was concentrated to a volume of 100 mL to give a precipitate which was washed with water, followed by 5% EtOAc/hexanes. A second crop was obtained from the filtrate upon further concentration. The two crops were combined and dried in vacuo to give the product as a white crystalline solid (10.4 g, 82%) of sufficient purity for use in the subsequent reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C1(C)C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][C:2]1=2
Reactant: O=C(O)CCCCc1cccs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: O=C1CCCCc2sccc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A mixture of 5-(2-thienyl)pentanoic acid (8.9 g, 48.0 mmol), phosphorus pentoxide (24.7 g, 86.9 mmol) and celite (16.0 g) in toluene (338 mL, 3170 mmol) was heated to reflux for 2 hr. The resulting black mixture was allowed to cool to rt and filtered. The solid cake was washed thoroughly with ethyl acetate then the filtrate was washed with saturated NaHCO3, dried over MgSO4, concentrated and dried under high vacuum to afford 6.0 g product as a brown oil (74.0% yield). LCMS: (FA) ES+ , 167. 1H NMR (400 MHz, CDCl3) δ: 7.40-7.42 (d, J=5.3, 2H), 6.98-7.00 (d, J=5.3, 2H), 3.0-3.12 (m, 2H), 2.72-2.76 (m, 2H), 1.85-2.0 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
A suspension of 2-methyl-5-nitrobenzotrifluoride (3.90 g, 19 mmol), N-bromosuccinimide (NBS, 3.56 g, 20 mmol), 2,2′-azobis(2-methylpropionitrile) (AIBN, 94 mg, 0.6 mmol) in CCl4 (40 mL) was refluxed under N2 for 16 h. HPLC indicated ca. 50% conversion. More NBS (10 mmol) and AIBN (0.6 mmol) was added, and the mixture was refluxed for another 14 h. HPLC indicated ca. 80% conversion. The reaction mixture was cooled down, and the solid was filtered off and washed with EtOAc. The combined filtrate was washed with aq. NaHCO3, dried over Na2SO4, filtered, concentrated on rotovap and further dried under vacuum. 1H NMR shows the ratio of desired product to unreacted 2-methyl-5-nitrobenzotrifluoride is 75:25. This material was not purified but used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH:9]=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To an ice cooled solution of [cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (12.3 g, 40 mmol) in THF (100 mL) was slowly added LAH (1M in THF; 45 mL), with the reaction mixture temperature maintained below 5° C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 20 min. A solution of NaHSO4 (7.3 g) in water (10 mL) was then slowly added to the reaction mixture to quench the reaction. The reaction mixture was then filtered through Celite. EtOAc (300 mL) was added to the filtrate, and the organic layer washed with aqueous NaCl solution, dried with MgSO4 and evaporated to yield (1-cyclohexyl-2-oxo-ethyl)-carbamic acid tert-butyl ester as an oil, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)cc2)CCN3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 29.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.32 g) was dissolved in methylene chloride (9.6 ml), m-chloroperbenzoic acid (87 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 210) (98 mg).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:22]=[C:21]2[C:16]([C:17]([Cl:27])=[CH:18][N:19]=[C:20]2[NH:23][C:24]([NH2:26])=[NH:25])=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C.C(Cl)Cl.[C:32]([C:36]([OH:38])=[O:37])([F:35])([F:34])[F:33]>>[F:33][C:32]([F:35])([F:34])[C:36]([OH:38])=[O:37].[Cl:27][C:17]1[C:16]2[C:21](=[CH:22][C:13]([S:10]([NH:9][CH2:8][CH2:7][C:6]([OH:28])=[O:5])(=[O:11])=[O:12])=[CH:14][CH:15]=2)[C:20]([NH:23][C:24]([NH2:26])=[NH:25])=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NCCC(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-β-alanine t-butyl ester (30 mg, 0.07 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 1 h. The mixture was evaporated in vacuo, azeotroping with PhMe, MeOH and then CH2Cl2, to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-β-alanine trifluoroacetate (32 mg, 0.066 mmol) as a white solid.