Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[CH:3]([OH:18])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:35]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[F:27][C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([F:26])[CH:23]=1)[CH2:19][C@H:2]([NH:1][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C@H:3]([OH:18])[CH2:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CCc1ccc2c(c1)C(NCC(O)C(N)Cc1cc(F)cc(F)c1)CCC2
Reactant: O=C1CCCC(=O)O1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)CCCC(=O)O)CCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 3-amino-4-(3,5-difluoro-phenyl)-1-(7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-butan-2-ol (0.240 g, 0.64 mmol), triethylamine (0.268 mL, 1.92 mmol), and chloroform (3 mL) was added glutaric anhydride (0.073 g, 0.64 mmol) and reaction was stirred overnight at 60° C. Reaction was washed with 1N HCl, 10% NaHCO3, brine, dried over MgSO4, filtered, concentrated in vacuo to give 5-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)amino]-5-oxopentanoic acid (100 mg). Purified via prep-HPLC. 1H NMR (400 MHz, CD3OD) δ 1.26 (t, J=8 Hz, 3H), 1.73 (m, 2H), 1.89 (m, 1H), 2.01 (m, 1H), 2.17 (m, 6H), 2.68 (d, J=8 Hz, 2H), 2.93 (d, J=6 Hz, 1H), 3.02 (m, 1H), 3.30 (m, 2H), 3.88 (m, 1H), 4.09 (m, 1H), 4.57 (m, 1H), 6.79 (m, 1H), 6.88 (m, 3H), 6.93 (d, J=6 Hz, 1H), 7.20 (m, 2H), 7.31 (s, 1H); OAMS: ES+ 488.9 ES− 486.9
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[OH-].[K+].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]=1Cl>CCO>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([S:9][C:14]2[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])[C:2]=1[NH2:1]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: Nc1c(S)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Cl)cccc1Sc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
The 2-amino-3-chlorobenzenthiol (550 mg, 3.95 mmol) was dissolved in EtOH (10 mL) followed by KOH (220 mg, 3.95 mmol). To this mixture was added a solution of 1,2-dichloro-3-nitrobenzene (760 mg, 3.95 mmol) in EtOH (10 mL). The resulting reaction mixture was refluxed for 8 h to 12 h. The reaction was allowed to cool to room temperature and the residue was extracted with EtOAc and 1 mol dm−3 H3PO4. The organic layer was dried over MgSO4, filtered and evaporated to give a crude material. This crude material was purified by flash silica gel chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19](F)[C:18](Cl)=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29][CH3:30])=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]([Cu])#[N:32].CN(C=O)C>CCOC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:31]#[N:32])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29][CH3:30])=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nnc(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nnc(-c2cc(C#N)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-iodo-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C, 18 mg, 0.034 mmol), CuCN (15 mg, 0.17 mmol), and DMF (500 μL). The reaction was then heated to 100° C. and stirred for 48 hours. The solution was then diluted with EtOAc and washed with an aqueous solution of EDTA (5% wt/wt). The organic layer was then concentrated and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-cyano-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide as a white solid: MS (ES) M+H expected 424.2, found 424.4.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH:20]=[O:21])=[N:14]2)=[CH:9][CH:8]=1>CCO.C(Cl)(Cl)Cl>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([CH2:20][OH:21])=[N:14]2)=[CH:9][CH:8]=1
Reactant: COCOc1ccc2ccc(C=O)nc2c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COCOc1ccc2ccc(CO)nc2c1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 46.3 %

Procedure:
Referring to FIG. 20, NaBH4 was added to a solution of 9a (18.1 mg, 0.0691 mmol) in absolute EtOH (5 mL). The reaction mixture was stirred for 15 min, diluted with chloroform, washed with water followed by brine. The organic layer was dried over Na2SO4 and the solvent was evaporated to afford 10a (8.3 mg, 0.032 mmol, 45%) as a yellow solid: 1H NMR (CDCl3) δ 8.14 (1H, d, J=8.8 Hz), 7.90 (1H, d, J=9.2 Hz), 7.58 (1H, d, J=9.2 Hz), 7.31 (1H, d, J=8.4 Hz), 5.39 (2H, s), 4.91 (2H, s), 3.54 (3H, s); 13C NMR (CDCl3) δ 162.4, 149.0, 139.1, 136.7, 131.9, 130.6, 123.1, 118.5, 116.3, 95.4, 64.5, 57.1; FTIR (neat) 3583, 2923, 1635, 1516, 1263, 1157, 1084, 1047, 931, 916, 804 cm−1; MS (ESI) m/z calculated for (C12H12N2O5+H)+ 265, found 265; HRMS (ESI) m/z calculated for (C12H12N2O5+H)+ 265.0824, found 265.0814.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[CH2:10][OH:11]>ClCCl.[O-2].[Mn+2]>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Nc1c(F)cc(Br)cc1CO
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1c(F)cc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of (2-amino-5-bromo-3-fluorophenyl)methanol (13 g, 59.4 mmol) and manganese oxide (31 g, 356.4 mmol) in dichloromethane (400 mL) was stirred at RT overnight. TLC showed the starting material consumed completely. The solid was filtered off, and the filtrate was concentrated to give the title compound (11 g, 85%) as a light yellow solid, which was directly used in the next step without further purification.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].[C:15](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)C)cc1Br
Yield: 102.3 %

Procedure:
Iodomethane (10.0 mL, 0.161 mol) was added to a mixture of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (29.5 g, 0.129 mol) and potassium carbonate (42.7 g, 0.309 mol) in dry acetone (400 mL) and the reaction mixture refluxed under nitrogen for 22 hours. The cooled reaction mixture was then concentrated and the residue partitioned between ethyl acetate (400 mL) and 0.3 M aqueous sodium hydroxide solution (300 mL). The organic phase was separated, washed with water (300 mL) and saturated brine (300 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-methoxybenzene (32.09 g, 100% yield) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 50.5 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 44.0 mg (0.131 mMol) 4-(acetyl)benzoic acid, 16.5 mg (50.5%) of the title compound were recovered.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-]>CN(C)C(=O)C>[CH2:16]([NH:23][CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CNCc3ccccc3)cnc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (35.7 mg, 0.106 mmol) in anhydrous N,N dimethylacetamide was added benzylamine (28.6 ul, 0.212 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 17.7 mg product was obtained. Yield: 62%; 1H NMR (500 MHz, DMSO-d6): δ 4.30499(s, 2H), 4.51599(s, 2H), 7.42787–7.47298(m, 3H), 7.50007–7.51927 (m, 2H), 8.87751(s, 1H); ESI-MS: m/z 282 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)c2ccc(Cl)cc2Cl)CC1

Procedure:
1-(2,4-dichlorophenyl)-2-chloroethan-1-one(1 mmol) and methylpiperazine (4 mmol) in 8 ml DMF was stirred for 8 h at room temperature. The reaction mixture was concentrated in vacuo and extracted into ethyl acetate and the organic layer was washed with water and dried with sodium sulfate. The residue after concentration in vacuo was purified by column chromatography eluting with 10% methanol in methylene chloride to yield 1-(2,4-dichlorophenyl)-2-(4-methylpiperazinyl)ethane-1-one. The ethanone was taken up in DMF-DMA and heated to 80° C. for 6 h. The reaction mixture was cooled and concentrated in vacuo and the residue containing the enaminone was purified by column chromatography. 1 mmol of the enaminone obtained above, 1 mmol of amino{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}carboxamidine hydrochloride and 3 mmol of Cs2CO3 was suspended in DMF and heated to 90° C. for fourteen hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the layers separated. The organic layers were dried with sodium sulfate and after solvent removal were chromatographed on silica gel eluting with 5-10% methanol in methylene chloride to obtain {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-(4-methylpiperazinyl)pyrimidin-2-yl]amine as a yellow powder after lyophilization.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8](F)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([NH2:22])C1C=CC=CC=1>C1C=CC=CC=1>[NH2:22][C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[C:11]([F:12])=[C:10]([F:13])[CH:9]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1c(F)cc(F)c(F)c1F
Solvent: c1ccccc1
Product: COC(=O)c1c(N)cc(F)c(F)c1F
Reaction time: 1.5 h

Procedure:
60 g of methyl 2,3,4,6-tetrafluorobenzoate and 70 g of benzylamine were reacted under reflux for 1 hour in 400 ml of benzene. After the reaction mixture was allowed to cool down, it was washed successively with water, 1% hydrochloric acid and 1% aq. sodium carbonate, each in the amount of 600 ml. The reaction mixture was treated with anhydrous magnesium sulfate and then concentrated. Crystals thus precipitated were collected by filtration and thereafter washed with methanol. 30 g of the crystals and about 2 ml of palladium/carbon were added to a liquid mixture which consisted of 100 ml of acetic acid and 200 ml of methanol. The resultant mixture was hydrogenated for 1.5 hours. The catalyst was filtered off and the filtrate was concentrated, whereby methyl 6-amino-2,3,4-trifluorobenzoate was obtained as a crystalline residue.
Reaction SMILES: Cl.[C:2]([CH2:4][NH2:5])#[N:3].[C:6](Cl)(=[O:10])[C:7]([Cl:9])=[O:8].Cl>O1CCOCC1>[C:2]([CH2:4][NH:5][C:6](=[O:10])[C:7]([Cl:9])=[O:8])#[N:3]
Reactant: N#CCN
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Product: N#CCNC(=O)C(=O)Cl

Procedure:
20 mM of cyanomethylamine hydrochloride and 25 mM of oxalyl chloride in 100 mM of absolute dioxane are heated at 60°-70° while passing through a stream of nitrogen. After one hour a clear solution results and there is no evidence of hydrogen chloride in the nitrogen stream. The solvent is evaporated under vacuum and the residual, light brown oil is taken up in methylene chloride, filtered over charcoal and stored at -30° until it is to be used.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].O>CN(C)C=O>[Si:22]([O:11][CH2:10][C@@H:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:12])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)Nc1cccc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
To a solution of (2S)-2-[(3-chlorophenyl)amino]propane-1-ol (7.00 g) in N,N-dimethylformamide (19 mL) were added imidazole (2.82 g) and tert-butyl(chloro)dimethylsilane (6.38 g), and the mixture was stirred at 50° C. for 14 hr. Water (200 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→40%) to give the title compound as a colorless oil (yield: 7.40 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: N#Cc1ccc(N)cc1F
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C#N)c(F)c1
Temperature: 120 °C

Procedure:
2-Fluoro-4-aminobenzonitrile (11.8 g) and 1-bromohexadecane (15.3 g) are dissolved in hexamethylphosphoramide (200 ml.) and heated under an atmosphere of nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water is added gradually. The mixture is then chilled in an ice-bath and filtered. The solid is washed thoroughly with water and dried. The solid is recrystallized from ether-hexane to yield 2-fluoro-4-(hexadecylamino)benzonitrile as a pale yellow solid.
Reaction SMILES: C(O[CH:5]([C:9]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:14]2[C:10]=1[CH2:11][N:12]([CH3:27])[C:13]2=[O:26])[CH2:6][CH:7]=[CH2:8])(=O)C.[Br-].[Br-].[Br-].[In+3].[CH2:32]([Si](C)(C)C)[CH:33]=[CH2:34]>C(Cl)Cl>[C:22]([O:21][C:19](=[O:20])[NH:18][C:15]1[CH:16]=[CH:17][C:9]([CH:5]([CH2:34][CH:33]=[CH2:32])[CH2:6][CH:7]=[CH2:8])=[C:10]2[C:14]=1[C:13](=[O:26])[N:12]([CH3:27])[CH2:11]2)([CH3:25])([CH3:24])[CH3:23]
Reactant: C=CC[Si](C)(C)C
Reactant: C=CCC(OC(C)=O)c1ccc(NC(=O)OC(C)(C)C)c2c1CN(C)C2=O
Agent: [Br-]
Agent: [In+3]
Solvent: ClCCl
Product: C=CCC(CC=C)c1ccc(NC(=O)OC(C)(C)C)c2c1CN(C)C2=O

Procedure:
To a solution of 1-{7-[(tert-butoxycarbonyl)amino]-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl}but-3-en-1-yl acetate (Compound 243E, 895 mg, 2.39 mmol) in DCM (30 mL) were added indium tribromide (85 mg, 0.24 mmol), followed by the addition of allyltrimethylsilane (550 mg, 4.8 mmol) in DCM (0.5 mL). The resulting mixture was refluxed under nitrogen overnight. The solvent was evaporated and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 10-50% EtOAc/Heptane) to give the desired product as a white solid, 180 mg. The unreacted starting material was recovered and resubjected to the reaction using 2.0 eq. allyltrimethylsilane and 0.2 eq. InBr3. The mixture was refluxed overnight. The solvent was evaporated and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 10-50% EtOAc/Heptane) to give the desired product as a white solid, 125 mg. Totally 305 mg, 36% yield. 1H NMR (CDCl3): 1.53 (s, 9H), 2.34-2.47 (m, 4H), 2.67 (m, 1H), 3.16 (s, 3H), 4.27 (s, 2H), 4.92-4.99 (m, 4H), 5.55-5.64 (m, 2H), 7.29 (d, J=8.6 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 9.52 (br s, 1H). MS (ES+): m/z=379.13 [MNa+]. HPLC: tR=4.83 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)=O>ClCCl>[C:2]1([NH:1][C@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)OS(=O)(=O)C(F)(F)F
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)Nc1ccccc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a stirred solution of aniline (4.55 mL, 50 mmol) and triethylamine (7 mL, 50 mmol) in anhydrous dichloromethane (120 mL) was added a solution of ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}propanoate (12.5 g, 50 mmol) in dichloromethane (60 mL) at 0° C. (Ice bath) over a period of 30 minutes under nitrogen. The ice bath was then removed and the reaction mixture was stirred at 35° C. for 2 h. The reaction mixture was cooled to rt, washed with water, dried over sodium sulfate, and evaporated to give desired product as oil (8.9 g, 92%) which was used as such for the next step. 1HNMR (300 MHz, CDCl3): δ 1.19-1.67 (m, 6H), 4.17-4.38 (m, 3H), 6.65-6.80 (m, 3H), 7.20-7.35 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:49][C:50]([C:52]1[C:60]2[N:59]=[C:58]([NH2:61])[NH:57][C:56]=2[CH:55]=[C:54]([S:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[C:60]2[NH:59][C:58]([NH:61][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:57][C:56]=2[CH:55]=[C:54]([S:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]
Reactant: CCOC(=O)c1cc(SCC)cc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(SCC)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 83 %

Procedure:
0.4 g (2.0 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.26 g (1.0 mmol) of 2-amino-6-ethylsulfanyl-1H-benzoimidazole-4-carboxylic acid ethyl ester as described in general procedure A to produce 0.35 g (0.83 mmol, 83%) of 6-ethylsulfanyl-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 421 (M+1)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:6]1([CH2:22][CH2:23][CH3:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][Si](C)(C)C)[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH2:4][CH3:5]>O.C(O)C>[CH2:22]([C:6]1([CH2:3][CH2:4][CH3:5])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[CH:17])[CH:14]=2)[S:9][CH2:8][CH2:7]1)[CH2:23][CH3:24]
Reactant: CCCC1(CCC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#Cc1ccc2c(c1)C(CCC)(CCC)CCS2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.82 g (32.4 mmol) of potassium hydroxide in 1.8 mL of water and 10.0 mL of ethanol was added to 1.22 g (3.70 mol) of (4,4-dipropylthiochroman-6-yl)(trimethylsilyl)acetylene (Compound 30) and the resulting mixture stirred at room temperature for 5 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aq H2SO4 and the product was extracted with 2×50 mL of ether.
Reaction SMILES: [C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[NH2:2].CO[CH:40](OC)[N:41]([CH3:43])[CH3:42]>C(Cl)Cl.O>[CH3:40][N:41]([CH:43]=[N:2][C:1]([CH:4]([CH2:32][CH2:33][C:34]([F:37])([CH3:36])[CH3:35])[CH2:5][CH:6]([O:28][C:29](=[O:31])[CH3:30])[CH:7]([NH:15][C:16]([C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:3])[CH3:42]
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(N)=O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(CC(CCC(C)(C)F)C(=O)N=CN(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of acetic acid 3-carbamoyl-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptyl ester (522 mg, 1.03 mmol) in N,N-dimethylformamide dimethyl acetal (2 mL) was heated to 50° C. for two hours, cooled to ambient temperature and diluted with methylene chloride and water. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound as a white foam (580 mg, 100%).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C1(C=O)CCCC1.Cl>N1C=CC=CC=1>[CH:9]1(/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: O=CC1CCCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/C1CCCC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of malonic acid (1.06 g, 10.2 mol) in pyridine (1.25 mL) was added piperidine (0.15 mL) and cyclopentanecarbaldehyde (1.00 g, 10.2 mmol). The mixture was heated to 40° C. for 2 hours, followed by stirring at room temperature for 16 hours. The mixture was then cooled in an ice bath and 2N HCl was added to acidify. The product was extracted with ether. The ether extract was washed with aq. HCl and brine, dried over sodium sulfate, filtered, and the solvent was removed in vacuo to afford the product (1.30 g, 77%), which was used without further purification.
Reaction SMILES: [OH:1][C:2]1([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:33])[CH:17]=3)=[CH:14][N:15]=2)[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:10])[CH3:9].Cl.[NH2:35][OH:36]>N1C=CC=CC=1>[OH:36]/[N:35]=[C:4]1/[C:3]([CH3:9])([CH3:10])[C:2]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:33])[CH:17]=3)=[CH:14][N:15]=2)([OH:1])[CH2:7][CH2:6][CH2:5]/1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCCC(=O)C3(C)C)s2)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC/C(=N\O)C3(C)C)s2)c1
Temperature: 60 °C
Yield: 96.8 %

Procedure:
A mixture of the product of Step 2 (300 mg, 0.63 mmol) and hydroxylamine hydrochloride (87 mg, 1.26 mmol) in pyridine (3 mL) was heated to 60° C. for 1 h, concentrated, and purified by flash chromatography to afford the title compound (301 mg, 0.61 mmol). MS ESI: [M+H]+ m/z 492.2. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.26 (s, 1H), 8.84 (d, J=4.9, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.48 (s, 1H), 7.29 (d, J=4.9, 1H), 7.16 (s, 1H), 5.97 (s, 1H), 2.82 (m, 1H), 2.33 (s, 3H), 2.24-2.38 (m, 2H), 1.65-1.85 (m, 3H), 1.08 (s, 3H), 1.07 (s, 3H). rhSYK activity=+++