Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30](OC)=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I.O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:34][CH3:37])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC1(c2ccc(Cl)cc2)CCN(CCC=C2c3ccccc3COc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example 2)(400 mg) in DMF (5 ml) were added sodium hydride (60% in oil, 50 mg), methyl iodide (0.07 ml) and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (100 mg).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[C:9]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:23])=[CH:7][C:5]=2[N:6]=1.[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[C:9]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:23])=[C:7]([F:25])[C:5]=2[N:6]=1
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2nc(Br)sc2c1O
Yield: 34.4 %

Procedure:
The reaction mixture of (S)-ethyl 2-(2-bromo-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75A) (380 mg, 0.948 mmol), Selectfluor (1.9 g, 4.74 mmol) in acetonitrile (7 ml) was reacted at 0° C. for 5 days. The reaction mixture was washed by 1.5 M KH2PO4, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-40% EtOAc in hexanes to give 75B (137 mg, 35%). LCMS-ESI+: calc'd for C16H19FNO4S: 420.0 (M+H+); Found: 420.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:10]=1[CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:22][OH:23].CCN(CC)CC>CO>[C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=[NH:17])[NH:22][OH:23])=[CH:11][C:10]=1[CH2:18][CH3:19])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCc1cc(C#N)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid tert-butyl ester (37.0 g, 135 mmol), hydroxylamine hydrochloride (14.1 g, 203 mmol) and NEt3 (27.4 g, 271 mmol) in MeOH (400 mL) is heated to reflux for 7 h before it is cooled to rt. The solvent is evaporated and the residue is taken up in isopropylacetate (500 mL) and washed twice with water (500 mL). The org. extract is dried over MgSO4, filtered, evaporated and dried to give 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester (40.8 g) as a pale yellow solid; 1H NMR δ 1.26 (t, J=7.5 Hz, 3H), 1.49 (s, 9H), 2.33-2.41 (m, 5H), 2.66-2.74 (m, 2H), 2.93-3.01 (m, 2H), 4.85 (s, 1H), 7.28 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:6]1=2.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH:32]2[CH3:37])=[CH:27][CH:26]=1.[I-].[K+]>C(O)(C)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[N:15][C:10]=4[CH2:9][O:8][C:7]4[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:6]3=4)[CH2:33][CH:32]2[CH3:37])=[CH:29][CH:30]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CC1CNCCN1c1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
A solution of 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.24 g, 0.64 mmol) in isopropanol (5 mL) was treated with 1-(4-Chloro-phenyl)-2-methyl-piperazine (0.25 g, 1.2 mmol) and catalytic potassium iodide. The solution was stirred at 80° C. for 5 hr, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate/methanol/triethylamine) to yield 0.22 g (69%) of the title compound, 1H-NMR (CDCl3) δ: 1.00 (3H, m), 1.60 (6H, s), 2.20–2.70 (8H, m), 3.10 (2H, m), 3.75 (1H, m), 5.30 (2H, brs), 6.12 (1H, t), 6.87(4H, d), 7.18–7.32 (3H, m), 7.45 (1H, s), 7.70 (1H, d), 8.55 (1H, d).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]Br.[Mg:12].C(Br)C[Br:15].ClCl>O1CCCC1>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH2:3][CH2:4][Mg:12][Br:15]
Reactant: CC(C)CCCC(C)CCBr
Reactant: BrCCBr
Reactant: [Mg]
Agent: ClCl
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CC[Mg]Br
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A tetrahydrofuran solution of 3,7-dimethyloctylmagnesium bromide was prepared from 6.64 g (0.03 mol) of 3,7-dimethyloctyl bromide, 0.73 g of metallic magnesium, 50 ml of tetrahydrofuran and 3 droplets of ethylene dibromide in a similar manner to that described in Example 1 and cooled to 5° C., followed by the addition of 0.6 g (0.003 mol) of CuBr·(CH3)2S. The obtained mixture was stirred at that temperature for 30 minutes. 50 ml of a solution of 3.4 g (0.02 mol) of 3-chloro-6-methylene-2-methyloctadiene-1,7 having a purity of 70% in tetrahydrofuran was dropped into the resulting mixture over a period of 30 minutes. After the completion of the dropping, the obtained mixture was stirred at that temperature for one hour and subjected to TLC and HPLC to confirm the disappearance of the chlorine-containing raw material.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(=O)CC.C(OCC)(=O)C>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])=[CH:25][CH:24]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.05 g, 3.73 mmol), 4-bromobenzyl bromide (1.21 g, 4.84 mmol) and cesium carbonate (1.84 g, 5.65 mmol) in 2-butanone (25 mL) was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography and eluted with hexanes/ethyl acetate (9:1, increased to 1:1) to afford 1′-(4-bromobenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.42 g, 84%) as a colorless solid: mp 148-150° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=8.4 Hz, 2H), 7.25-7.17 (m, 4H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.12 (s, 1H), 5.89 (s, 1H), 5.88 (s, 1H), 5.02 (d, J=15.6 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.78 (d, J=15.6 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 177.8, 156.1, 149.1, 142.5, 141.9, 134.9, 132.3, 132.2, 129.3, 129.1, 124.2, 123.8, 122.0, 119.4, 109.3, 103.1, 101.7, 93.8, 80.6, 58.4, 43.7; MS (ES+) m/z 452.0 (M+1), 450.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:9]([F:12])([F:11])[F:10])([C:5]([F:8])([F:7])[F:6])[OH:4].C([Li:19])CCC>CCCCCC>[F:1][C:2]([F:13])([F:14])[C:3]([C:5]([F:7])([F:8])[F:6])([C:9]([F:12])([F:11])[F:10])[O-:4].[Li+:19]
Reactant: [Li]CCCC
Reactant: OC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Product: [Li+]
Product: [O-]C(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Yield: 88 %

Procedure:
A stirred mixture of 11.8 g (0.05 mol) of 2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethanol in 40 ml of hexane was cooled to -10°, and 0.05 mol of butyllithium in hexane (1.6 M) was added dropwise. The reaction mixture was warmed to 25°, and the solid precipitate was collected on a filter and dried under a stream of dry nitrogen to give 10.69 g (88% of lithium 2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxide, mp 139° to 141° (dec.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([OH:6])=[O:5].O=S(Cl)[Cl:9].[CH2:11](O)[CH2:12][CH3:13]>>[ClH:9].[NH2:2][CH2:3][C:4]([O:6][CH2:11][CH2:12][CH3:13])=[O:5]
Reactant: CCCO
Reactant: O=S(Cl)Cl
Reactant: NCC(=O)O
Agent: Cl
Product: CCCOC(=O)CN
Temperature: 70 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
To a solution of glycine hydrochloride 46 (4.5 g, 40.3 mmol) in n-propanol (60 mL) was slowly added SOCl2 (13.5 mL) at room temperature. The reaction mixture was stirred at 70° C. for 15 h. After cooling to room temperature, the mixture was evaporated under vacuum to provide the titled compound (6.1 g, 98%) as a white solid. MH+118.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][C:6]1([CH2:11][CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4].[Br-].[OH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([S+:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]2=3)=[CH:17][C:16]=1[CH3:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.ClCCl>[Br-:1].[CH2:11]([C:6]1([O:5][C:3](=[O:4])[CH2:2][O:14][C:15]2[C:16]([CH3:35])=[CH:17][C:18]([S+:22]3[C:23]4[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]3=4)=[CH:19][C:20]=2[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:12]
Reactant: CCC1(OC(=O)CBr)CCCC1
Reactant: Cc1cc(-[s+]2c3ccccc3c3ccccc32)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(OC(=O)COc2c(C)cc(-[s+]3c4ccccc4c4ccccc43)cc2C)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
1-ethylcyclopentyl 2-bromoacetate (4.03 g, 17.1 mmol, 1.1 eq) was added dropwise to a solution of 5-(4-hydroxy-3,5-dimethylphenyl)-5H-dibenzo[b,d]thiophenium bromide (6.00 g, 15.6 mmol) and cesium carbonate (10.15 g, 31.1 mmol, 2 eq) in dimethylformamide (150 mL) under N2 at 0° C. The solution was slowly warmed to r.t. and stirred for 16 h. The reaction mixture was diluted with water (400 mL) and dichloromethane (400 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (4×150 mL). The combined organic layers were extracted with water (2×300 mL), dried (Na2SO4) and concentrated to the remaining DMF (−100 mL). This non-viscous solution was slowly poured onto MTBE (700 mL) under vigorous stirring. The precipitate was filtered, washed with MTBE (3×200 mL) and the residue dried in vacuo to afford the title compound (7.92 g, 94%) as a white solid. 1H NMR (500 MHz, d-DMSO) δ: 8.51 (d, J=8 Hz, 2H), 8.32 (d, J=7.5 Hz, 2H), 7.96 (t, J=7.5 Hz, 2H), 7.75 (t, J=7.5 Hz, 2H), 7.31 (s, 2H), 4.51 (s, 2H), 2.21 (s, 6H), 1.93-2.03 (m, 2H), 1.92 (q, J=7 Hz, 2H), 1.49-1.69 (m, 6H), 0.79 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.FC(F)(F)S(O[Si:20]([CH3:23])([CH3:22])[CH3:21])(=O)=O.CCOCC>ClCCl>[CH3:21][Si:20]([CH3:23])([CH3:22])[O:6][C:2](=[CH:3][CH2:4][CH3:5])[CH3:1]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC=C(C)O[Si](C)(C)C
Yield: 25.7 %

Procedure:
In 500 mL of dichloromethane, was dissolved 22.0 mL (207 mmol) of 2-pentanone. While stirring the resulting solution in an ice bath, 44 mL (317 mmol) of triethylamine was added to the solution, and then, 42 mL (232 mmol) of trimethylsilyl trifluoromethanesulfonate was added dropwise to the solution. After the addition of trimethylsilyl trifluoromethanesulfonate, the mixture was stirred for 1 hour at room temperature, poured into ether (500 mL)/a saturated aqueous sodium hydrogencarbonate solution (300 mL) so as to extract the ether layer. The ether layer was washed with saturated sodium chloride water and water, dried over sodium sulfate anhydride, filtered, and concentrated. The residue was distilled under normal pressure to collect fractions of 110 to 125° C. As a result, 8.43 g (53.2 mmol, 49.4%) of 2-trimethylsilyloxy-2-pentene was obtained. According to a similar method, 5.33 g (33.6 mmol, 32.3%) of 2-trimethylsilyloxy-2-pentene was obtained from 11.0 mL (103.8 mmol) of 2-pentanone.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3([C:19]#N)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[C:5]2[CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][C:4]=2[NH:3]1.C[Mg]Br.[Cl-].[NH4+].[Cl:35]CCl>O1CCCC1.O>[ClH:35].[CH3:19][C:13]1([N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C:5]4[CH:21]=[C:22]([O:25][C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:24][C:4]=4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: N#CC1(N2CCC(n3c(=O)[nH]c4ccc(OC(F)(F)F)cc43)CC2)CCOCC1
Reactant: ClCCl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(N2CCC(n3c(=O)[nH]c4ccc(OC(F)(F)F)cc43)CC2)CCOCC1
Product: Cl
Reaction time: 2 h

Procedure:
4-{4-[2-Oxo-6-(trifluoromethoxy)-2,3-dihydro-1H-benzimidazol-1-yl]piperidin-1-yl}tetrahydro-2H-pyran-4-carbonitrile (D36, 62 mg) in tetrahydrofuran (5 ml) was treated with 3M methylmagnesium bromide solution in tetrahydrofuran (0.3 ml) and stirred for 2 hours. A second aliquot of 3M methylmagnesium bromide solution in tetrahydrofuran (0.3 ml) was added and the solution was stirred for 2 hours, then treated with saturated ammonium chloride solution (3 ml). The mixture was treated with dichloromethane and water. The dichloromethane layer was separated, dried by passing through a 3 g hydromatrix cartridge and the solvent was removed. The residue was dissolved in methanol and treated with hydrogen chloride in ether to give a white solid which partitioned between dichloromethane and sodium bicarbonate solution. The dichloromethane layer was separated, dried by passing through a hydromatrix cartridge and the solvent was removed. The residue was treated with hydrogen chloride in ether to give the title compound as a white solid (28 mg). M+ 400.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][N:21]=[CH:22][C:15]=2[N:14]=[C:13]1[CH:23](Br)[CH:24]([CH3:26])[CH3:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>CN(C=O)C>[N:1]([CH:23]([C:13]1[N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][N:21]=[CH:22][C:15]=2[N:14]=1)[CH:24]([CH3:26])[CH3:25])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)C(Br)c1nc2cnccc2c(=O)n1Cc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C(N=[N+]=[N-])c1nc2cnccc2c(=O)n1Cc1ccccc1
Temperature: 65 °C

Procedure:
To a solution of sodium azide (1.41 g, 21.7 mmol) in DMF (12 mL) was added 3-benzyl-2-(1-bromo-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (5.4 g, 14.50 mmol) in DMF (12 mL). The reaction was heated to 65° C. for 1.5 h, and then the solution was cooled to room temperature. The reaction contents were poured into a separatory funnel filled with ether and ice water. The organic solution was washed with brine and dried over sodium sulfate. Filtration and concentration afforded the title compound as a brown oil. 1H NMR (500 MHz, CDCl3) δ 0.61 (d, J=6.5 Hz, 3H), 1.09 (d, J=6.5 Hz, 3H), 2.67-2.73 (m, 1H), 3.71 (d, J=10 Hz, 1H), 5.10 (d, J=16.5 Hz, 1H), 5.83 (d, J=16 Hz, 1H), 7.16 (d, J=8 Hz, 2H), 7.32-7.38 (m, 3H), 8.12 (d, J=6.5 Hz, 1H), 8.75 (d, J=5.5 Hz, 1H), 9.13 (s, 1H). MS [M+H] C18H18N6O=335.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N>C(O)(=O)C.ClC(Cl)C>[CH2:11]([NH:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1sc(NCc2ccccc2)c(C#N)c1C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (151 mg, 1.0 mmol) and benzaldehyde (106 mg, 1 mmol) in 15 mL of 4% acetic acid in dichloroethane was added silica supported cyanoborohydride (2.0 g. 2.0 mmol). The reaction was placed in a microwave reactor for 5 minutes at 135° C. Silica supported cyanoborohydride was removed by filtration, and the product was purified by prep HPLC using acetonitrile/water as solvent. MS 243 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11](Cl)[C:10]=1[C:24]#[N:25].[C:26]([O-:29])(O)=O.[Na+]>CO.N1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11]([N:12]2[CH2:13][CH2:26][O:29][CH2:10][CH2:11]2)[C:10]=1[C:24]#[N:25]
Reactant: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(Cl)nc2n(C)c1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCN1
Product: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(N3CCOCC3)nc2n(C)c1=O
Temperature: 80 °C

Procedure:
An amount of 50 mg (0.117 mmole) of 47a was dissolved in 500 μL, of MeOH, 1 ml of morpholine and 512 mg (6.203 mmole) of NaHCO3. The mixture was heated to 80° C. for 1 hr to give 5-(2-Bromo-5-fluoro-phenyl)-1,3-dimethyl-7-morpholin-4-yl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (47b).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:11][C:12](=[O:35])[CH:13]([C:24](=[O:34])[N:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:23])[NH2:22])=[CH:17][CH:16]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(#N)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].ClCCl>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:27]([N:25]([CH3:26])[C:24]([CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:22])[NH2:23])=[CH:17][CH:16]=1)[C:12]([NH:11][C@@H:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:3]([OH:36])=[O:2])=[O:35])=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N(C)Cc1ccccc1)C1CCCCC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
22.1 g (44.8 mmol) of the above [2-(R,S)-(Benzyl-methyl-carbamoyl)-3-(4-carbamimidoyl-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester was suspended in water/concentrated hydrochloric acid (1/1, 40 ml) and acetonitrile (40 ml) was added to give a solution. The reaction mixture was stirred at room temperature for 7 days. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel with dichloromethane/methanol/TFA as solvent to give the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][O:3]1.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19](Cl)[N:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19]([N:8]([CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:13])([CH3:1])[O:6]2)[S:9]([CH3:12])(=[O:10])=[O:11])[N:18]=1
Reactant: CC1(C)OCC(CNS(C)(=O)=O)O1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N(CC2COC(C)(C)O2)S(C)(=O)=O)nc(Cl)n1
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methane sulfonamide (0.875 g, 4.18 mmol) in DMF (25 mL) was added 60% NaH in mineral oil (0.193 g, 4.83 mmol). After 10 minutes, methyl 2,6-dichloropyrimidine-4-carboxylate (0.871 g, 4.21 mmol) was added. After stirring for 30 minutes, the reaction mixture was diluted into 100 mL water and extracted three times with 50 mL EtOAc. The combined organic layers were washed once with 25 mL brine, dried over MgSO4, filtered, and evaporated to a residue. The residue was chromatographed over silica gel with 30-60% EtOAc in hexanes. The product fractions were concentrated in vacuo. After sitting overnight a crystalline solid formed. The solid was decanted and dried under vacuum to give methyl 2-chloro-6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methylsulfonamido)pyrimidine-4-carboxylate as a cream-colored powder (0.911 g, 2.40 mmol, 57% yield). LC/MS: m/z=380.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: NCCCCO
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCCO

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 4-amino-1-butanol (21 ul) according to Method A to give a material which was re-purified by reversed phase C-18 HPLC in absence of trifluoroacetic acid to give the title compound (19 mg). 1H-NMR (400 MHz, CD3OD) d 7.75 (s, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.28-7.18 (m, 5H), 7.04 (d, J=8.8 Hz, 1H), 4.79 (s, 2H), 4.51 (m, 1H), 4.24 (dd, J=5.2 Hz, J=9.2 Hz, 1H), 3.52 (m, 1H), 3.18 (m, 1H), 3.09-2.92 (m, 4H), 2.75 (m, 1H), 1.45 (m, 4H), 1.36 (s, 9H); HRMS m/z 601.2616 (calc. of monoisotopic mass for C30H39N3O10 gives 601.2635).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C:9]([CH3:15])([CH3:14])[N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[I:16][CH3:17]>CC(C)=O>[I-:16].[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C:9]([CH3:15])([CH3:14])[N+:10]([CH3:17])=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: CC1(C)Cc2ccc([N+](=O)[O-])cc2C=N1
Solvent: CC(C)=O
Product: C[N+]1=Cc2cc([N+](=O)[O-])ccc2CC1(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-Nitro-3,3-dimethyl-3,4-dihydroisoquinoline (1.0 g, 4.9 mmol) in acetone (100 ml) was treated with iodomethane (1 ml, 16 mmol). The mixture was stirred at 25° C. for 18 h and the resultant precipitate collected by filtration and dried; pale yellow powder (1.5 g, 88%).