Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:10][C:11]#[N:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1>CO.[Ni]>[C:3]1([CH2:7][CH2:8][NH2:9])[CH:4]=[CH:5][CH:6]=[C:1]([CH2:10][CH2:11][NH2:12])[CH:2]=1
Reactant: N#CCc1cccc(CC#N)c1
Agent: [Ni]
Solvent: CO
Product: NCCc1cccc(CCN)c1
Reaction time: 48 h
Yield: 95.9 %

Procedure:
To a solution of 1,3-phenylenediacetonitrile (9.37 g, 60 mmol) in CH3OH (saturated with NH3, 150 mL) was added Raney-Ni (ca. 20 g, previously washed with CH3OH several times) and the mixture was hydrogenated at 45 psi on a Parr apparatus for 48 h. The reaction mixture was filtered through celite and the filtrate evaporated to give the crude product (9.45 g, 96%) as a light green oil: 1H NMR (CDCl3) δ0.80-1.50 (br s, 4H), 2.70-2.76 (m, 4H), 2.94-2.99 (m, 4H), 7.01-7.07 (m, 3H), 7.18-7.26 (m, 1H). This was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([C@H:9]1[C:31](=[O:32])[N:11]2[CH:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[C:13]([OH:17])([CH3:16])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([C@H:9]1[C:31](=[O:32])[N:11]2[CH:12]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[O:19])[C:13]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:16])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8]
Reactant: CC1(O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(OS(C)(=O)=O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
A solution of CH3SO2Cl (34 μl, 0.44 mMol) in anhydrous CH2Cl2 (0.5 ml.) is added dropwise over 4 min. to an ice-cold, stirring solution of p-nitrobenzyl 7α-azido-3-hydroxy-3-methyl-cepham-4-carboxylate (135 mg., 0.34 mMol) and Et3N (71 μl, 0.51 mMol) in anhydrous CH2Cl2 (2 ml.). After stirring 15 more min. in the cold, the reaction mixture is diluted with cold CH2Cl2 (2 ml.), washed with ice-cold H2O (2 ml.), ice-cold 5% HCl (2 ml.), and ice-cold 5% NaHCO3 (2 ml.), dried over MgSO4, and filtered. Evaporation of the solvent in vacuo gives p-nitrobenzyl 7α-azido-3-methanesulfonyloxy-3-methyl-cepham-4-carboxylate (156 mg.) as a pale yellow oil: ir (CHCl3) 4.76, 5.62, 5.75, 6.57, 7.40, 8.47, and 11.1μ; nmr (CDCl3) δ2.10 (s, 3, CH3), 2.93 (s, 3, SO2CH3), 3.02 (d, l, J=14Hz, SCH), 3.87 (d, l, J=14Hz, SCH), 4.53 (d, l, J=1.2Hz, H7), 4.80 (s, l, H4), 4.97 (d, l, J=1.2Hz, H6), 5.35 (s, 2, CH2Ar), and 7.60, 8.28 (two d's 4, J=8.7Hz, ArH).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:37])([F:36])[C@H:30]([OH:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][C@@H:30]([OH:35])[C:29]([F:37])([F:36])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)C[C@@H](O)C(F)(F)F
Agent: Cl
Product: O=C(C[C@@H](O)C(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (133 mg, 94%), MS (ISP) m/z=471.5 [(M+H)+], mp 214.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (R)-4,4,4-trifluoro-3-hydroxybutanoic acid.
Reaction SMILES: C([Mg]Br)C.[CH:5](=[N:12][CH2:13][C:14]#[CH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>O1CCCC1.[Cl-].[Na+].O>[CH:5](=[N:12][CH2:13][C:14]#[C:15][Si:17]([CH3:19])([CH3:18])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCN=Cc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCN=Cc1ccccc1
Reaction time: 0.5 h

Procedure:
10 g of ethyl magnesium bromide was added over 30 minutes to a stirred solution of 10.2 g of 1A in 100 ml of tetrahydrofuran at 0° C. The resulting mixture was stirred at that temperature for 30 minutes, then a solution of 7.75 g of trimethylsilyl chloride in 30 ml of tetrahydrofuran was added over 30 minutes. The mixture then was stirred at 0° C. for 90 minutes, treated with brine, dried (MgSO4) and the solvent was evaporated. The residue was distilled at 85°-90° C., 0.3 Torr., to give N-benzylidene-3-(trimethylsilyl)-2-propyn-1-amine (1B), as a water-white oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:26]3[O:25][CH:24]([CH3:27])[C:23](=[O:28])[N:22]([CH3:29])[C:21]=3[CH:20]=[C:19]([Cl:30])[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH+:14]([O-:39])[C:15]([C:17]2[C:26]3[O:25][CH:24]([CH3:27])[C:23](=[O:28])[N:22]([CH3:29])[C:21]=3[CH:20]=[C:19]([Cl:30])[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1Oc2c(C(=O)NC3CCN(Cc4ccccc4)CC3)cc(Cl)cc2N(C)C1=O
Solvent: ClC(Cl)Cl
Product: CC1Oc2c(C(=O)[NH+]([O-])C3CCN(Cc4ccccc4)CC3)cc(Cl)cc2N(C)C1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2.7 g of N-(1-benzyl-4-piperidyl)-6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide in 150 ml of chloroform is added portionwise 2.7 g of metachloroperbenzoic acid under cooling and stirring. After 0.5 hour, ammonia gas is bubbled through the reaction solution under stirring and the precipitate is filtered off. The mother liquor is distilled off under reduced pressure followed by recrystallizing the residue from ethanolisopropyl ether to give N-(1-benzyl-4-piperidyl)-6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide N-oxide.
Reaction SMILES: C1(NC(=[S:10])NC)CCCC1.[CH:11]1([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1>[CH:20]1([NH:19][C:18]([NH:17][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[S:10])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CNC(=S)NC1CCCC1
Solvent: C1COCCO1
Product: S=C(NC1CCCCC1)NC1CCCCC1

Procedure:
2.44 g of N-[4 -(β-<2-methoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-methyl-thio-urea (I) were dissolved together with 1.03 g of dicyclohexylcarbodiimide in 20 ml of hot dioxane. The whole was allowed to cool and to stand for several days. Thereupon, the N,N'-dicyclohexyl-thiourea that had formed (melting point 176° - 178° C) was filtered off with suction. The filtrate which contained the N-[4-(β-<2-methoxy-5-methyl-benzamido>ethyl)-benzenesulfonyl]-N'-cyclopentyl-methyl-carbodiimide (II) in dissolved state, was combined with about 5 ml of water. The whole was shortly heated on a water bath and concentrated. The residue was dissolved in a mixture of toluene, ether and dilute aqueous ammonia, while shaking. The aqueous phase was separated. The toluene/ether phase was extracted again with dilute ammonia. The aqueous extracts were united and acidified. There was obtained a precipitate, constituting the N-[4-(β-<2-methoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentylmethylurea (III). After recrystallization from methanol, the sulfonylurea was found to melt at 148° - 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[CH2:9]([NH2:12])[CH2:10][NH2:11]>C(Cl)(Cl)Cl>[NH2:11][CH2:10][CH2:9][NH:12][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NCCN
Reactant: Fc1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: NCCNc1ccc(Cl)cc1
Temperature: 200 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
4-Chlorofluorobenzene (92.00 g) and ethylenediamine (290.0 g) were placed in a pressure-resistant stainless-steel reactor. A stirrer was placed in the reactor and the reactor was sealed. Subsequently, the reaction mixture was stirred for 2 days at an external temperature of 200° C. The reaction mixture was allowed to cool, and chloroform (800 ml) was added to the mixture. The mixture was transferred to a separating funnel, washed sequentially with water (200 ml), saturated brine (200 ml), and a saturated sodium hydrogencarbonate solution (100 ml) in this order. The aqueous layer was extracted with chloroform (200 ml×3), washed with saturated brine, combined with the chloroform layer again, and dehydrated over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, to thereby yield the target compound (116.69 g) as a pale-yellow oily product, Since this product contained almost no impurities and was considered to be almost pure by NMR, the product was submitted to the next reaction step without further purification.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5](=[O:22])[C@@H:6]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][C:8](Cl)=[O:9]>CCOCC.C1COCC1.[Cu]I>[CH3:3][O:4][C:5](=[O:22])[C@@H:6]([NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][C:8](=[O:9])[CH3:1]
Reactant: [Li]C
Reactant: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
To a cooled to 0° C. suspension of copper (I) iodide in ether (20 mL) under N2 is slowly added methyl lithium (1.6 M solution in ether, 21.3 mmol, 13.3 mL). The mixture is stirred at 0° C. for 10 min then cooled to −78° C. A solution of 3.55 mmol of (S)-2-Benzyloxycarbonylamino-3-chlorocarbonyl-propionic acid methyl ester (Ref: Synth. Comm 1993, 23(18), 2511-2526) in 12 mL of dry THF is added drop wise. The mixture is stirred at −78° C. for 30 min then quenched by adding methanol (2 mL). The mixture is poured into saturated NH4Cl (80 mL) and extracted with ether (2×40 mL). The organic layers are dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 35 g silica gel, eluted with EtOAc:Heptane (1:1) to afford (S)-2-benzyloxycarbonylamino-4-oxo-pentanoic acid methyl ester (261 mg, 26%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][CH2:9][NH:10][OH:11].[C:12](Cl)(=[O:14])[CH3:13].C(N(CC)CC)C.[Li+].[OH-]>CC(O)C>[OH:11][N:10]([CH2:9][CH2:8][O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:12](=[O:14])[CH3:13]
Reactant: ONCCOCc1cccs1
Reactant: CC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)N(O)CCOCc1cccs1

Procedure:
The title compound is prepared from 2-(thien-2-ylmethoxy)ethyl hydroxylamine from Example 19 by first reaction with 3 equivalents of acetyl chloride and 3.3 equivalents of triethylamine followed by treatment with LiOH in 2-propanol.
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([O:22][CH3:23])(=[O:21])[C:15]#[C:16][C:17]([O:19][CH3:20])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(=O)C>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]1[C:14]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Temperature: 115 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
A 300 mL RBF was charged with N,N-Dimethylacetamide (DMA) (144 ml) and Acetic Acid (48.1 ml) was degassed with O2 for 5 min. To this was added aniline (2.94 ml, 32.2 mmol), dimethyl but-2-ynedioate (3.96 ml, 32.2 mmol), and Pd(OAc)2 (0.723 g, 3.22 mmol) and the reaction was heated to 115° C. under an atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of celite, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol, 39.9% yield) as a yellow solid. The indole was dissolved in DMF (50 mL), treated with Cs2CO3 (6.30 g, 19.33 mmol), 4-Fluorobenzyl chloride (1.929 ml, 16.11 mmol) and KI (5.35 g, 32.2 mmol) and heated to 90° C. After 2 h, the reaction mixture was cooled to ambient temperature and partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water (5×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylate (3.79 g, 11.10 mmol, 34.5% yield) as a yellow solid. LCMS (m/z) ES+=342 (M+1).
Reaction SMILES: [Br:1][C:2](=[CH2:5])[CH:3]=O.BrBr.[NH2:8][C:9]1[C:18]([Br:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:20][CH3:21])[CH:10]=1>CC(O)=O>[Br:1][C:2]1[CH:3]=[N:8][C:9]2[C:10]([CH:5]=1)=[C:11]([O:20][CH3:21])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][C:18]=2[Br:19]
Reactant: C=C(Br)C=O
Reactant: COC(=O)c1cc(Br)c(N)cc1OC
Agent: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c2ncc(Br)cc2c1OC
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
step 1—Bromine (4.48 mL, 86.9 mmol) in HOAc (50 mL) was added to a solution of 2-bromoacrylaldehyde (11.7 g, 86.9 mmol, CASRN 111049-68-4) in HOAc (100 mL) at RT until the solution showed faint Br2 color. To this solution was added methyl 4-amino-5-bromo-2-methoxybenzoate (22.6 g, 86.9 mmol) and the resulting solution was gradually heated to 100° C. After the temperature reached 100° C., stirring was continued for 15 min then the solution was cooled and concentrated in vacuo. The reaction mixture was neutralized with satd. aq. NaHCO3 and the resulting solid was filtered and washed with water. The solid was washed with ether followed by 10% MeOH/DCM to afford 11.04 g of 122a. The filtrate was absorbed onto SiO2 and purified on a flash column eluting with a DCM/hexane gradient (50 to 100% DCM to afford an additional 3.46 g of 122a.
Reaction SMILES: [IH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([CH2:14][CH2:15][OH:16])[C:12](SC)=[N:11][CH2:10]1.[NH3:19]>CO>[IH:1].[NH2:19][C:12]1[N:13]([CH2:14][CH2:15][OH:16])[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[CH2:10][N:11]=1
Reactant: CSC1=NCC(c2ccccc2Cl)N1CCO
Reactant: N
Agent: I
Solvent: CO
Product: NC1=NCC(c2ccccc2Cl)N1CCO

Procedure:
A mixture of 18.3 parts of 5-(o-chlorophenyl)-2-(methylthio)-2-imidazoline-1-ethanol hydroiodide and 40 parts of methanol saturated with ammonia is stirred and refluxed for 2 hours. The solvent is evaporated and the solid residue is treated with 20 parts of 2-propanol. The product is filtered off and recrystallized from 50 parts of water, yielding 2-amino-5-(o-chlorophenyl)-2-imidazoline-1-ethanol hydroiodide, m.p. 181.6°C.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[C:3]1(/[CH:2]=[CH:1]/[C:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17]3[NH:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C(=Cc1ccncc1)c1ccccc1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C1=C(/C=C/c2ccccc2)CCN(Cc2nc3ccccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-styrylpyridine (4.0 g, 22.1 mmol) and 2-chloromethylbenzimidazole (3.7 g, 22.1 mmol) in dimethylformamide (20 ml) was heated at 110°-120° C. under a nitrogen atmosphere for 1.5 hours. The mixture was cooled to room temperature, diluted with ethanol (380 ml) and carefully treated with sodium borohydride (880 mg, 23.2 mmol). The mixture was stirred at room temperature for 2 hours, then heated at reflux for 1 hour before stirring at room temperature overnight. The ethanol was evaporated in vacuo and the residue partitioned between ethyl acetate (100 ml) and sodium carbonate (half saturated, 100 ml). The phases were separated and the aqueous was extracted with ethyl acetate (2×100 ml). The combined organics were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give a reddish gummy residue which was purified by flash chromatography (eluting with 5% methanol in dichloromethane) to give a yellow gummy solid. The gum was triturated with ethyl acetate and recrystallised from ethyl acetate to give the title compound as a mustard solid (912 mg, 13%). M.p. 225°-227° C. (EtOAc); (Found: C, 79.74; H, 6.89; N, 13.47. C21H21N3 requires C, 79.97; H, 6.71; N, 13.32%); δH (DMSO-d6) 2.37 (2H, br s, tetrahydropyridinyl CH2), 2.69 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.17 (2H, br s, tetrahydropyridinyl CH2), 3.83 (2H, s, NCH2Ar), 5.91 (1H, s, CH=CR), 6.48 (1H, d, J 16.2 Hz, CHCHPh), 6.91 (1H, d, J-16.2 Hz, CHPh), 7.13-7.22 (3H, m, ArH), 7.29-7.33 (2H, m, ArH), 7.42-7.47 (3H, m, ArH), 7.54 (1H, m, ArH), and 12.31 (1H, br s, NH); m/z (CI+, NHs) 316 (M+1)+.
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])(=O)C.[K+]>C(#N)C>[C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)cc2)cc1
Temperature: 75 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-iodophenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (i), 317 mg) in acetonitrile (5 mL) under nitrogen was treated with 4-methoxyphenylboronic acid (96 mg) followed by an aqueous solution of potassium acetate (2M, 0.65 mL) and 1,1 bis(bi-tert-butylphosphino)ferrocene palladium dichloride (8 mg). The reaction mixture was stirred at 75° C. for 18 h and then evaporated, dissolved in dichloromethane and absorbed onto silica. Purification by chromatography on silica eluting with 50% ethyl acetate in isohexane and then 100% ethyl acetate afforded the sub-titled compound as a solid (120 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)C5CC5)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A187) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].Cl.[O:25]([NH2:27])[CH3:26].N1C=CC=CC=1>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[S:15][C:6]1[CH:5]=[C:4]([C:1](=[N:27][O:25][CH3:26])[CH3:2])[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CON
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Yield: 82.3 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (0.9 g), methoxylamine hydrochloride (0.21 g) and pyridine (0.2 g) in ethanol (15 ml) was refluxed for 4 hours. The mixture was concentrated under reduced pressure, and the residue was triturated with water to give a powder. The powder was recrystallized from ethanol to give 2'-(2,4-difluorophenylthio)-4'-[1-(methoxyimino)ethyl]methanesulfonanilide (0.8 g).
Reaction SMILES: [NH:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3]1.Cl.Cl.N[CH:15]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:16]([NH:18][C:19]1([C:26]#[N:27])[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[O:17]>C1COCC1>[C:26]([C:19]1([NH:18][C:16](=[O:17])[CH:15]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]=2)[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)#[N:27]
Reactant: N=C1NC(=O)c2ccccc21
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NC(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-imino-2,3-dihydro-isoindol-1-one and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 10, except that refluxing THF was used as the solvent. The compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 422.5=M+1.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2].C(Cl)(=O)C>CC(C)=O>[Br:14][C:11]1[CH:10]=[C:6]2[C:5]([CH2:4][C:1](=[O:2])[O:8][C:7]2=[O:9])=[CH:13][CH:12]=1
Reactant: O=C(O)Cc1ccc(Br)cc1C(=O)O
Solvent: CC(C)=O
Solvent: CC(=O)Cl
Product: O=C1Cc2ccc(Br)cc2C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a suspension of 2-(carboxymethyl)-5-bromobenzoic acid (2.37 g) in acetone (20 ml) was added acetyl chloride (2.60 ml) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and azeotroped with toluene (×3). The resultant solid was triturated with diethyl ether to yield 7-bromo-1H-isochromene-1,3(4H)-dione as a brown solid (2.20 g); NMR Spectrum: (DMSOd6) 4.24 (s, 2H), 7.42 (d, 1H), 7.94 (d, 1H), 8.13 (s, 1H).