Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16].CCOC(C)=O>CN(C=O)C.C1COCC1.[Cl-].[Na+].O>[OH:1][NH:2][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1
Reactant: NO
Reactant: O=C(O)CCCCC=C(c1ccccn1)c1ccccn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCCCC=C(c1ccccn1)c1ccccn1)NO
Temperature: 25 °C
Reaction time: 17 h

Procedure:
HONH2 (50% aqueous, 0.3 mL) was added to IV (32 mg, 0.1 mmol) in DMF (0.3 mL) and THF (0.3 mL) at 0° C. The reaction mixture was stirred at rt for 17 h, after which brine (3 mL) and EtOAc (3 mL) were added. The phases were separated, and the aqueous phase was extracted with EtOAc (2×3 mL). The organic phases were then combined, dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using CH2Cl2/MeOH (100:3 to 100:10) as eluant to furnish V, a colourless oil (9.6 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C(=O)CBr)c1
Product: COC(=O)Cc1c(C(=O)c2cc(CO)ccn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine (Preparation is described in step 1 of Example 95).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:8]=1[N:18]1[CH:22]=[C:21]([C:23]([NH:25][CH:26]2[CH2:28][CH2:27]2)=[O:24])[N:20]=[N:19]1.O>CN(C=O)C>[CH:26]1([NH:25][C:23]([C:21]2[N:20]=[N:19][N:18]([C:8]3[CH:9]=[CH:10][C:11]([C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[CH:12][C:7]=3[O:6][CH:5]=[CH2:4])[CH:22]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=COc1cc(C(=O)NCC)ccc1-n1cc(C(=O)NC2CC2)nn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
To a suspension of sodium hydride (0.06 g, purity 60%) in DMF (5 ml) was added 1-{2-(2-chloroethoxy)-4-[(ethylamino)carbonyl]phenyl}-N-cyclopropyl-1H-1,2,3-triazole-4-carboxamide (0.19 g) obtained in Example 150, and the mixture was stirred at 0° C. for 30 min and at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) and recrystallized from ethanol-water to give the title compound as a pale-yellow powder (0.02 g, 13%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[CH:20]=[C:19]3[C:27](=O)[CH:28]([CH3:30])[CH2:29][C:18]=23)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].Cl.C1C=CC=CC=1.CCOC(C)=O>CCOCC>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[CH:20]=[C:19]3[CH:27]=[C:28]([CH3:30])[CH2:29][C:18]=23)=[CH:15][CH:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC1Cc2c(cc3c(c2-c2ccc(C(C)(C)C)cc2)CCCC3)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1=Cc2cc3c(c(-c4ccc(C(C)(C)C)cc4)c2C1)CCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
LiAlH4 (0.95 g, 25 mmol) was added at −20° C. to the solution of 4-(4-tert-Butylphenyl)-2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-1-one (16.6 g, 50 mmol) in Et2O (150 ml). Resulting mixture was allowed to warm to room temperature and stirred for additional 1 h. Then 5% HCl (100 ml) was added, the resulting mixture was extracted by Et2O (3 times of 50 ml). Combined organic phases were washed by water, dried over MgSO4 and evaporated. Benzene (300 ml) and p-TSA (0.5 g) were added, and resulting solution was refluxed with Dean Stark head (control by TLC, benzene/EtOAc 4:1) within 4 h. Then the resulting solution was washed by water, aq. KHCO3, water, dried over MgSO4, passed through silica gel and evaporated giving 12.8 g (81%) of product.
Reaction SMILES: Cl.Cl.Cl.[OH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH:6]1[N:11]1[CH2:16][CH2:15][C:14]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].[I:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>C(O)C>[I:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:8]2[CH2:9][CH2:10][CH:5]([OH:4])[CH:6]([N:11]3[CH2:16][CH2:15][C:14]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:19][CH2:18][CH2:17]4)[CH2:13][CH2:12]3)[CH2:7]2)=[CH:35][CH:34]=1
Reactant: ClCc1ccc(I)cc1
Reactant: OC1CCNCC1N1CCC2(CCCc3ccccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC1CCN(Cc2ccc(I)cc2)CC1N1CCC2(CCCc3ccccc32)CC1

Procedure:
A mixture of the hydrochloride of 21c (250 mg, 0.67 mmol), potassium carbonate (463 mg, 3.35 mmol) and 4-iodobenzyl chloride (298 mg, 1.00 mmol) in absolute ethanol (25 mL) was refluxed for 16 h. When the mixture had cooled, salts were filtered off and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and the solution was successively washed with water (25 mL) and brine (25 mL). The organic layer was then dried (Na2SO4) and concentrated. The product was purified by chromatography (silica gel, hexanes/ethyl acetate: 50/50) and (13e) was obtained as a colorless oil (226 mg, 52%). The hydrochloride was prepared in a satd HCl/ether soln and recrystallized twice from 50% isopropyl alcohol-hexanes to yield a yellow powder; mp 256.3° C.; 1H NMR (CDCl3)δ1.56-2.18 (2 m, 8, 2 N--CH2 --CH2 ), 2.40-2.45 (d, 2H, Ar--CH2CH2, J=10.1 Hz), 2.51-2.60 (m, 2, CH2 --CHOH), 2.72-2.78 (m, 4, Ar--CH2 --CH2 --CH2), 2.84-2.97 (t, 2, N--CH2 --CH2 --CHOH, J=11.9 Hz), 3.05-3.50 (d, 2, CHN-CH2--N, J= 10.4 Hz), 3.40-3.55 (m, 4, CH--OH+Ar--CH2 --N+CHN), 3.81 (s, 1, OH), 7.22-7.02 (m, 4, arom.), 7.42-7.46 (d, 2, arom., J=7.7 Hz), 7.63-7.67 (d, 2, arom., J=8.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][N:14](C=O)C.C(OCC)(=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[NH2:1][C:2]1[C:3]([C:13]#[N:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)cnc1Cl
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(C(F)(F)F)cc1N
Temperature: 150 °C
Reaction time: 0.67 h

Procedure:
A mixture of 5.14 g of 3-amino-2-chloro-5-trifluoromethylpyridine, 3.92 g of zinc cyanide, 1.19 g of tris(dibenzylideneacetone)dipalladium(0), 1.45 g of 1,1′-bis(diphenylphosphino)ferrocene and 20 ml of DMF was stirred at 150° C. for 40 minutes. Ethyl acetate and water were added to the cooled reaction fixture, and the mixture was filtered. The aqueous layer of the filtrate was extracted with ethyl acetate, then combined with the organic layer of the filtrate and washed with water, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and then the resulting residue was applied to a silica gel column chromatography to obtain 2.23 g of 3-amino-2-cyano-5-trifluoromethylpyridine.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17].F[B-](F)(F)F.[C:27]1(=[O:41])[N:31](OC(N(C)C)=[N+](C)C)[C:30](=[O:40])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][N:31]1[C:27](=[O:41])[CH2:28][CH2:29][C:30]1=[O:40])=[O:17]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: COC(=O)CCCCCCCCCCCCCCC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 20 h
Yield: 96.8 %

Procedure:
Mono-methyl hexadecandioate (275 mg, 0.91 mmol) was dissolved in THF (3 ml) and treated with succinimidyl tetramethyluroniumtetrafluoroborate (331 mg, 1.1 mmol) and N,N-diisopropylethylamine (188 μL, 1.1 mmol), and the mixture was stirred for 20 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate and washed with 0.1 M HCl (twice) and water. The organic phase was dried over MgSO4, filtered and evaporated in vacuo to give 350 mg (96%) of methyl succinimidyl hexadecandioate.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:24])[C@H:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:12]C(OC(C)(C)C)=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([NH:9][C:10](=[O:24])[C@H:11]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH2:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)NCCc1ccccc1
Reaction time: 6 h

Procedure:
N-(tertiarybutoxycarbonyl)-L-leucine N-phenethylamide (6.17 g, mole) was dissolved in a 1:1 TFA/CH2Cl2 mixture (60 ml). After stirring for 6 h at 20° the reaction mixture was concentrated in vacuo and the residue in CH2Cl2 (50 ml) washed with saturated aq. NaHCO3 (100 ml). The aqueous extract was back extracted with CH2Cl2 (50 ml×3) and the combined organic extracts concentrated to an oil in vacuo. The crude L-leucine N-phenethylamide so obtained was used as such in the next step.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.[Cl-].[Na+].O.CCCCCC.C(OCC)(=O)C>[CH2:46]([NH:53][C:14](=[O:16])[C@@H:2]([NH:1][C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[C:10]([F:11])([F:12])[F:13])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)NCc1ccccc1
Reaction time: 0.08 h
Yield: 102.5 %

Procedure:
A solution of Boc-Lys(Tfa)-OH (Compound tk96) (104 mg, 0.304 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (HOBT) (61.6 mg, 0.456 mmol) in DMF (0.5 mL) was cooled in an ice bath under a nitrogen atmosphere, followed by addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI.HCl) (87 mg, 0.456 mmol). The reaction mixture was stirred at the same temperature for 5 minutes, followed by addition of benzylamine (40 μL, 0.365 mmol). The reaction mixture was stirred at room temperature for 17.5 hours, followed by addition of ethyl acetate, hexane and brine. The resulting mixture was extracted with ethyl acetate, and the organic phase was washed with brine (1 mL×2) and then dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-tert-butyl (1-(benzylamino)-1-oxo-6-(2,2,2-trifluoroacetamido)hexan-2-yl)carbamate (Compound tk97) (134.4 mg, quant.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-])=O)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]=[N:10][C:11]=2[C:16]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])ccc2c1ncn2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole (8 g) in methanol (40 mL)/ethyl acetate (400 mL)is added palladium-on-carbon (Pd/C) (10%, 0.5 g) and ammonium formate (7.27g). The mixture is stirred at 50° C. for 2 hours, then filtered on Celite, with methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between water and ethyl acetate. The organic layer is washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and rotary evaporated to afford pure 5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]1[CH:59]=[C:60]([CH:63]=[CH:64][CH:65]=1)[CH2:61][NH2:62])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([NH:62][CH2:61][C:60]1[CH:63]=[CH:64][CH:65]=[C:58]([O:57][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:59]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1cccc(OCc2ccccc2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCc1cccc(OCc2ccccc2)c1
Reaction time: 18 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)methionine (1.20 g, 4.8 mmol) in dry CH2Cl2 (25 mL) under argon were added PYBOP (2.90 g, 5.6 mmol), 3-benzyloxybenzylamine, as described above in Step I, (1.0 g, 4.7 mmol), and N,N-diisopropylethylamine (0.89 mL, 5.1 mmol). The reaction mixture was stirred for 18 hours, then extracted with saturated aqueous NaHCO3 (25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—25% EtOAc to yield the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([O:18]C)=[O:17])=[C:4]([F:20])[CH:3]=1.C1COCC1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=[O:17])=[C:4]([F:20])[CH:3]=1
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
The product from Step 1 (503 mg, 1.70 mmol, 1.00 equiv) was dissolved in 3/1 MeOH:THF (8 mL total). Following addition of 2.5N NaOH (2 mL), the reaction mixture was heated to 60° C. for 6 hours, then stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed again with 1N NaOH. The aqueous phases were combined and acidified to pH˜1 with 5N HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with satd. NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated en vacuo and azeotroped several times with hexanes to afford 252 mg (52%) of the acid as an off-white solid. MS (ES+) m/e 284 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].Cl[C:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1.O>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[C:5]([N:2]([CH3:1])[NH2:3])=[N:6][C:7]([S:16][CH3:17])=[N:8][CH:9]=1)=[O:12])[CH3:15]
Reactant: CNN
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(SC)nc1N(C)N
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of methyl hydrazine (4.0 g, 0.087 mol, 2 eq) in ethanol (50 mL) was slowly added to a solution of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (10 g, 0.043 mol) in ethanol (50 mL) while keeping the reaction temperature below 15° C. After the addition was completed, the reaction mixture was stirred for 2 hours at the room temperature. Water (100 mL) was then added and the formed product was isolated by filtration. After drying, the product was recrystalized from a 1:1 toluene-hexane mixture to give 7.3 g (69%) of the desired 4-(N-methyl-hydrazino)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester; LC/MS (m/e)=243.1 (MH+), Rt=1.15 min.
Reaction SMILES: CO.[OH-].[Na+].C([O:7][C:8]([C:10]1([C:17]([O:19]CC)=[O:18])[CH2:15][CH:14]2[CH2:16][CH:11]1[CH:12]=[CH:13]2)=[O:9])C>O1CCCC1>[C:17]([C:10]1([C:8]([OH:9])=[O:7])[CH2:15][CH:14]2[CH2:16][CH:11]1[CH:12]=[CH:13]2)([OH:19])=[O:18]
Reactant: CCOC(=O)C1(C(=O)OCC)CC2C=CC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(C(=O)O)CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
A mixture of methanol (12 ml), 10% aqueous sodium hydroxide (12 ml), tetrahydrofuran (12 ml) and 2,2-bisethoxycarbonyl-5-norbornene (2.38 g) was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was diluted with water, made acidic with 10% hydrochloric acid (HCl) solution and extracted with ether. The extract was washed with water and dried. Removal of the solvent gave as an oil 2,2-dicarboxy-5-norbornene (Compound No. 2-1) (1.63 g). IRνmaxfilm (cm-1): 2990, 1710, 1340.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].N(CCO)CCO.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CS(C)=O.[Pd](Cl)Cl.C([O-])(=O)C.[Na+].O.CC1C=CC(C)=CC=1>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CS(C)=O
Solvent: OCCNCCO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 83.2 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate were heated to 120° C. with 50 ml of p-xylene, 40 ml of diethanolamine and 10 ml of water. At 80° C., a mixture of 19.3 mg of palladium chloride, 17.9 mg of sodium acetate and 0.55 ml of TPPTS/ H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.5 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7](OS(C2C=CC=CC=2S(N(CC)C2CCN(CC3C=CC=CC=3)C2)(=O)=O)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15](=[NH:17])[NH2:16].CC1C=C2C(NC(=O)C2=C(OCCCOC2C=CC=CC=2[O:70][S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[S:80]([N:83]([CH2:96][CH3:97])[CH:84]2[CH2:88][CH2:87][N:86]([CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[CH2:85]2)(=[O:82])=[O:81])(=[O:73])=[O:72])C=1)=O.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:70][S:71]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[S:80]([N:83]([CH2:96][CH3:97])[CH:84]2[CH2:88][CH2:87][N:86]([CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[CH2:85]2)(=[O:81])=[O:82])(=[O:73])=[O:72])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1ccc(C)cc1OCCCONC(=N)N
Reactant: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1ccccc1OCCCOc1cc(C)cc2c1C(=O)NC2=O
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: CCN(C1CCN(Cc2ccccc2)C1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Yield: 83 %

Procedure:
N-{3-[5-Methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl) phenylsulfonyloxy]phenoxy]propoxy}guanidine dihydrochloride: The title compound was prepared in 83% yield from N-{3-[5-methyl-3-[(2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxyphthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 11.15 (br s, 2H), 8.18 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.00 (t, J=7.6 Hz, 1H), 7.88 (t, J=7.7 Hz, 1H), 7.68 (br s, 4H), 7.38 (m, 5H), 6.74 (s, 1H), 6.52 (s, 1H), 6.48 (s, 1H), 4.66 (br s, 1H), 4.04 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.89 (t, J=6.3 Hz, 2H), 3.50 (m, 2H), 2.75-3.20 (m, 5H), 2.21 (s, 3H), 2.13 (m, 2H), 2.01 (pentet, J=6.2 Hz, 2H), 1.10 (t, J=6.9 Hz, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C30H39N5O7S2: 646.2 (M+H). Found: 646.0.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:14]Br>C(Cl)Cl>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([OH:13])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=1
Reactant: Oc1ccccc1OC1CCCC1
Reactant: BrBr
Solvent: ClCCl
Product: Oc1ccc(Br)cc1OC1CCCC1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
A solution of 2-(cyclopentyloxy)phenol intermediate (5.6 g, 31 mmol) in CH2Cl2 (40 mL) at −78° C. was treated dropwise with a solution of bromine (4.9 g, 31 mmol) in CH2Cl2 (10 mL) via addition funnel over a 1 h period. After warming up to room temperature gradually over 3 h, the reaction was quenched by addition of a saturated aqueous solution of Na2S2O4. The isolated organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The crude mixture was then purified by ISCO (0-10% EtOAc in hexanes) to afford intermediate 4-bromo-2-(cyclopentyloxy)phenol (2.6 g, 32%) as colorless oil. 1H NMR (300 MHz, CDCl3) 6.97-6.93 (m, 2H), 6.78 (d, J=9.3, 1H), 5.54 (s, 1H), 4.78 (m, 1H), 1.95-1.63 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:6][C:5]([N:18]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][N:3]=1.Cl>C1COCC1>[NH2:18][C:5]1[CH:6]=[C:7]([NH:8][S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl)N1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cnc(Cl)c(NS(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
The two batches of N-(2-chloro-5-(diphenylmethyleneamino)pyridin-3-yl)morpholine-4-sulfonamide (total 0.47 g, 1.0 mmol) were placed in two 150 mL round-bottomed flasks. To each flask were added 1 N hydrochloric acid (0.6 mL each, total 1.2 mL) and 3 mL THF (3 mL each, total 6 mL). After stirring at room temperature for 10 min, the two reaction mixtures were combined and most of THF was removed in vacuo, and the residue was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (30 mL). The aqueous phase was extracted with 25% isopropanol in chloroform (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (25 g, eluent: iPrOH in CHCl3 0% to 10%) to afford N-(5-amino-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.233 g, 77% yield) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.64 (d, J=2.74 Hz, 1H) 7.30 (d, J=2.74 Hz, 1H) 6.68 (br. s., 1H) 3.83 (br. s., 2H) 3.66-3.71 (m, 4H) 3.22-3.27 (m, 4H). m/z (ESI, positive ion): 293.0 (M+H)+.