Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:8][CH:7]=[CH:6][C:5]=1[C:21]1[S:22][CH2:23][C@:24]([CH3:31])([C:26]([O:28]CC)=[O:27])[N:25]=1>CO>[OH:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:8][CH:7]=[CH:6][C:5]=1[C:21]1[S:22][CH2:23][C@:24]([CH3:31])([C:26]([OH:28])=[O:27])[N:25]=1
Reactant: CCOC(=O)[C@@]1(C)CSC(c2cccc(OCCOCCOCCOC)c2O)=N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOCCOCCOc1cccc(C2=N[C@@](C)(C(=O)O)CS2)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
A solution of 50% (w/w) NaOH (13.88 mL, 266.02 mmol) in CH3OH (120 mL) was added to 13 (8.89 g, 20.80 mmol) in CH3OH (280 mL) with ice bath cooling. The reaction mixture was stirred at room temperature for 6 h, and the bulk of the solvent was removed by rotary evaporation. The residue was treated with dilute NaCl (300 mL) and the basic aqueous phase was cooled in ice, acidified with 2 N HCl to pH=2, and extracted with EtOAc (4×150 mL). After the EtOAc layers were washed with saturated NaCl (300 mL), glassware that was presoaked in 3 N HCl for 15 min was employed henceforth. After solvent removal by rotary evaporation, purification was done on C-18 reverse phase column, eluting with 50% aq. methanol and lyophilized to furnish 4.98 g of 9 (60%) as an orange oil: [α]20+61.9°; 1H NMR (D2O) δ 1.77 (s, 3H), 3.35 (s, 3H), 3.56-3.62 (m, 3H), 3.64-3.73 (m, 4H), 3.75-3.89 (m, 2H), 3.92-3.96 (m, 2H), 3.99 (d, 1H, J=11.6), 4.25-4.31 (m, 2H), 6.99 (t, 1H, J=8.2), 7.26-7.33 (m, 2H); 13C NMR δ 24.52, 39.93, 59.07, 69.04, 69.83, 70.49, 70.64, 70.86, 71.97, 83.21, 116.33, 117.94, 118.50, 122.80, 147.67, 150.24, 172.38, 176.10; HRMS m/z calcd for C18H26NO7S, 400.1429 (M+H). found, 400.1413.
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:15][C@@H:14]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=4[CH3:31])[CH2:20][CH2:19]3)=[O:17])[NH:13][C:12]2=[O:32])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:15][C@@H:14]([C:16]([N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=4[CH3:31])[CH2:22][CH2:23]3)=[O:17])[N:13]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:12]2=[O:32])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)CC4CCCCC4)C(=O)N3)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)CC4CCCCC4)C(=O)N3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-1-cyclohexylmethanesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one (100 mg) in CH2Cl2 (3 mL) was added cupric acetate (39 mg) and triethylamine (60 μl), followed by phenyl boronic acid (53 mg). The reaction mixture was stirred at room temperature for 16 hours. Additional phenyl boronic acid (53 mg) and triethyl amine (60 μl) was added and stirring was continued for 16 hours at room temperature. The mixture was concentrated in vacuo and the residue was purified by chromatography (SiO2, n-heptane/ethyl acetate 1:1) to give (S)-1-(cyclohexylmethanesulfonyl)-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-imidazolidin-2-one as a white solid. MS: 539.0 ([M+H]+)
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([OH:7])=[O:6].[CH3:8][CH:9]([CH:11]1[CH2:13][CH2:12]1)[OH:10].O>C1COCC1>[CH:11]1([CH:9]([O:10][CH2:4][C:5]([OH:7])=[O:6])[CH3:8])[CH2:13][CH2:12]1
Reactant: CC(O)C1CC1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(OCC(=O)O)C1CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
To a suspension of NaH (80% in oil) (15.7 g, 523 mmol) in THF (180 mL) at 0° C. were added bromoacetic acid (28.0 g, 203 mmol) and a-methylcyclopropane methanol (10.0 g, 116 mmol). The resulting mixture was then stirred at 70° C. After a period of 18 h, the reaction mixture was poured over cold H2O and the H2O phase was extracted once with Et2O. The water phase was acidified with HCl and extracted twice with Et2O. The ether was dried over MgSO4, filtered and evaporated under reduced pressure. The crude oil was then purified by flash chromatography (40% EtOAc in hexane to 40% EtOAc in Hexane+AcOH) to provide 5.0 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18](Cl)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([N:22]([CH3:21])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2nc(C(=O)Cl)c3ccc(I)cc32)n1
Reactant: CNc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carbonyl chloride (330 mg, 0.83 mmol) in DCM (5 mL) was added N-methylpyridin-2-amine (0.1 ml, 0.99 mmol) followed by triethylamine (0.29 ml, 2.06 mmol). The reaction was stirred at RT overnight and then concentrated in vacuo. The residue was diluted with water (10 ml) and extracted with DCM (2×20 ml). The title intermediate was obtained as a precipitate which was collected by suction filtration. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The precipitate and organic extracts were combined to give the crude title intermediate; LC-MS purity=79%: 1H NMR (500 MHz, DMSO) delta 3.54 (3H, s), 6.28 (1H, d, J=5.5 Hz), 7.15 (2H, s), 7.25 (1H, dd, J=6.7, 5.0 Hz), 7.40 (1H, d, J=8.1 Hz), 7.74 (1H, dd, J=8.5, 1.3 Hz), 7.79-7.84 (2H, m), 8.19 (1H, d, J=5.5 Hz), 8.32 (1H, dd, J=4.6, 1.5 Hz), 9.24 (1H, s); LC-MS: m/z=+472.00 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].[CH3:11]O>>[NH2:1][CH2:2][CH2:3][S:4][CH2:5][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[NH2:7]
Reactant: CO
Reactant: NCCSC[C@H](N)C(=O)O
Product: COC(=O)[C@@H](N)CSCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 10 g (50 mmol) sample of S-(2-aminoethyl)-L-cysteine was dissolved in 400 mL of methanol. Into this cooled solution was bubbled in anhydrous HCl for 30 minutes. After stirring at room temperature overnight, the solution was concentrated to afford 12.7 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:9]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 60 °C

Procedure:
A mixture of 5-Nitroindazole (1.00 g, 6.13 mmol) was dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (2.50 g, 18.1 mmol) was stirred for 30 minutes after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.56 g 9.17 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature. The mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4) and the filtrate concentrated in vacuo. The residue was purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) ppm 1.64 (m, 4H), 2.48 (m, 4H), 2.99 (t, 2H, J=6.44), 4.62 (t, 2H, J=6.44), 7.78 (m, 1H), 8.00 (m, 1H), 8.83(m, 1H), 8.88 (m, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:10]1=[O:26])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:10]1=[O:26])[CH3:2]
Reactant: CCC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-ethyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.34 g, 0.93 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (2.16 mL, 28 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles, the residue was dissolved in dichloromethane (2 mL) and treated with hydrogen chloride (2 mL, 4 N in dioxane) and the mixture was concentrated to give 2-(4-ethyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LC/MS: (M+1)+: 265.16.
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[N:13]3[CH2:17][CH2:18][NH:19][C:12]3=[N:11][C:10]=2[N:9]([CH3:20])[C:8]1=[O:21].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C)C=O>[CH3:20][N:9]1[C:10]2[N:11]=[C:12]3[NH:19][CH2:18][CH2:17][N:13]3[C:14]=2[C:15](=[O:16])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([O:1][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH3:22])[C:8]1=[O:21]
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
To the stirring solution of (R)-7,8-dihydro-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-13430) (200 mg, 0.65 mmol) and imidazole (68 mg, 1.0 mmol) in dimethylformamide (1 ml) was added tert-butyldimethylsilyl chloride (127 mg, 1.30 mmol). After stirred at room temperature for 16 hours, the reaction mixture was treated with water and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with water (2×5 ml), with saturated aqueous sodium chloride solution (5 ml), and dried over magnesium sulfate. Concentrating under reduced pressure to provide (R)-7,8-dihydro-1-methyl-3-(5-tert-butyldimethylsilyloxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H, 6H)-dione (280 mg, 100% yield) as a white powder.
Reaction SMILES: S1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH2:8])=[NH:7].[CH3:9][C:10]1C=CN=C(C#N)[CH:11]=1>>[CH3:11][C:10]1[CH:5]=[CH:4][N:3]=[C:2]([C:6]([NH2:8])=[NH:7])[CH:9]=1
Reactant: N=C(N)c1nccs1
Reactant: Cc1ccnc(C#N)c1
Product: Cc1ccnc(C(=N)N)c1

Procedure:
4-Methyl-pyridine-2-carboxamidine (Compound A2) was prepared in analogy to compound thiazole-2-carboxamidine with the procedure shown in Scheme 5 by using 4-methyl-pyridine-2-carbonitrile instead of thiazole-2-carbonitrile. MS: calc'd (MH+) 136, measured (MH+) 136.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([OH:25])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([N:17]2[CH2:20][CH:19]([C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:22]([O:25][CH3:34])([CH3:24])[CH3:23])[CH2:18]2)[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(O)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(C)(C)[C@H](c1cc(F)cc(F)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 46.6 mg (0.1 mmole) of 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile in THF was cooled to −78° C. To this was added 0.3 mL of a 1M solution of NaHMDS in THF. After 10 minutes, 20 uL of iodomethane was added and the solution was allowed to warm to rt. The solution was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was filtered through silica gel using 10% ethyl acetate-hexane to afford the title compound; 1H-NMR(CDCl3) δ 1.07 (s, 3H), 1.14 (S, 3H), 2.28 (t, 1H, J=7.5 Hz), 2.74 (d, 1H, J=10.7 Hz), 2.82 (t, 1H, J=7.5 Hz), 3.10-3.16 (m, 2H), 3.19 (s, 1H), 3.62 (m, 1H), 4.29 (s, 1H), 6.67-6.73 (m, 3H), 7.21-7.4 (m, 8H);); Mass Spectrum: m/e=481 (M+1, 35Cl) and 483 (M+1, 37Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18]1>>[S:17]1[CH:21]=[CH:20][C:19]([CH2:22][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:18]1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Reactant: OCc1ccsc1
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCc1ccsc1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and 3-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [CH3:1][NH:2][NH2:3].O=[C:5]([CH2:11][C:12](=O)[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)C>[CH3:1][N:2]1[C:12]([CH3:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:3]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(C)n1
Temperature: 0 °C

Procedure:
9.2 ml of methylhydrazine was added dropwise over 30 minutes to a solution of 25 g of ethyl 2,4-dioxovalerate in 36 ml of ethanol, the temperature of the mixture being kept below 40° C. by cooling in an ice bath. The resulting solution was heated at reflux for 23 hours, poured into 300 ml of ice water and the resulting mixture was extracted with ether. The extract was dried (MgSO4), filtered and stripped of solvent. The residue was chromatographed on silica gel, with a 1:1 v:v mixture of ethyl acetate and hexane as eluent. The middle fractions gave ethyl 1,5-dimethylpyrazole-3-carboxylate (39A), as a yellow oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].O>CN(C=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])=[C:4]([I:9])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Oc1cnc(F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Cool a suspension of 6-fluoro-4-iodo-pyridin-3-ol (1.5 g, 6.28 mmol) and K2CO3 (4.38 g, 31.4 mmol) in DMF (10 mL) to 0° C. in an ice bath under nitrogen. Add 2-(2-bromo-ethyl)-isoindole-1,3-dione (3.19 g, 12.55 mmol). Stir the mixture at RT overnight. Add water. Extract with ethyl acetate. Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (hexane to 30% ethyl acetate in hexane) to afford the title compound as a yellow oil (1.51 g, 58%). MS (ES) m/z 413 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH3:15])[CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)=[O:5])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:31][NH:32][C:33](=[O:45])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[NH2:35].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:31][NH:32][C:33](=[O:45])[C@H:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)[NH:35][C:8](=[O:10])[CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:15]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CCOC(=O)C(C)C(CC(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Temperature: 0 °C

Procedure:
A mixture of 3-(ethoxycarbonyl)-2-(2-methylpropyl)butanoic acid (7.5 g., 0.037 mol.) and dichloromethane (70 mls.) was stirred and cooled to 0° C. To the mixture was added dropwise a solution of N,N'-dicyclohexylcarbodiimide (7.6 g., 0.37 mol.) in dichloromethane (20 mls.) and the reaction mixture was allowed to warm to room temperature. A solution of O-methyl-L-tyrosine N-methylamide (7.7 g., 0.037 mol.) in dichloromethane (45 mls.) was added to the reaction mixture and the resulting mixture was stirred overnight at room temperature. A saturated sodium bicarbonate solution (100 mls.) was added to the reaction mixture and the resulting mixture was stirred for an additional hour. The reaction mixture was filtered and the organic layer recovered and then dried on anhydrous sodium sulfate. The solvent was removed by evaporation in vacuo to yield a sticky brown solid. The solid was purified by chromatography on normal phase silica eluting with 20% hexane in ethyl acetate to yield N-[3-(ethoxycarbonyl)-2-(2-methylpropyl)butanoyl]-O-methyl-L-tyrosine N-methylamide as a mixture of 4 diastereomers.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:9][NH:10][C:11](=[O:21])[O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[CH:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:9][NH:10][C:11](=[O:21])[O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[C:15]([CH3:20])[CH:14]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: CCCCS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1ccc(OC(=O)NC)cc1C

Procedure:
Butanesulfonyl chloride (2.6g., 0.017 mole) was added dropwise to a mixture of 3-methyl-4-aminophenyl N-methylcarbamate (3.0g., 0.017 mole), triethylamine (1.85g., 0.018 mole) and benzene (50 ml.). After refluxing for two hours, the reaction mixture was washed in a separatory funnel with water. The organic phase was dried with anhydrous magnesium sulfate and upon removal of the solvent the product was isolated as a dark oil (3.15g.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.I.[OH-].[Na+]>C(O)(=O)C>[Cl:12][C:4]1[N:3]=[CH:2][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1cc2ccccc2cn1
Temperature: 170 °C
Reaction time: 3 h

Procedure:
A mixture of 1,3-dichloroisoquinoline (26.0 g; prepared according to the method of G Simchen, Angew. Chem. Internat. Ed. 5 (7), 663, 1966), acetic acid (125 ml), hydrogen iodide (55 ml) and red phosphorus (9.0 g) was heated with stirring at a temperature of 170° C. for a period of 3 hours. After cooling the mixture was poured into ice-water and the aqueous mixture was neutralized with aqueous sodium hydroxide. The aqueous mixture was extracted with dichloromethane and the organic extract was dried over anhydrous magnesium sulfate. The solvent was evaporated to give an oil which was purified by column chromatography over silica gel (eluant dichloromethane) to give 3-chloroisoquinoline (18.23 g) mp<50° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][N:15]([C:25]3[N:26]=[N:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=3)[C:12]2=[CH:13][N:14]=1.[BH4-].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([CH:18]([OH:24])[CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:16][N:15]([C:25]3[N:26]=[N:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=3)[C:12]2=[CH:13][N:14]=1
Reactant: CCC(CC)C(=O)c1cn(-c2ccc(OC(C)C)nn2)c2cnc(-c3c(C)cccc3C)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(CC)C(O)c1cn(-c2ccc(OC(C)C)nn2)c2cnc(-c3c(C)cccc3C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[5-(2,6-dimethyl-phenyl)-1-(6-isopropoxy-pyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one (70 mg, 0.15 mmol) in a (4:1) EtOH—H2O mixture (5 mL) cooled to −30° C., NaBH4 (50 mg, 1.3 mmol) is added, and the mixture is allowed to gradually warm up to room temperature at which the stirring is continued for 2 h. The mixture is concentrated tinder reduced pressure. The residue is diluted with a saturated aqueous solution of Rochelle's salt (10 mL), and the product is extracted with DCM. The combined organic solutions are washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Chromatography of the residue on silica gel (hexane-EtOAc, 1:1) gives 1-[5-(2,6-dimethyl-phenyl)-1-(6-isopropoxy-pyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-ol as colorless oil. 1H NMR (CDCl3) 9.52 (s, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.22-7.10 (m, 3H), 5.62 (m, 1H), 5.21 (m, 1H), 2.08 (s, 6H), 1.47 (d, J=7 Hz, 6H), 1.08 (s, 9H); LCMS m/z 459.14 (2.48 min).
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-])=O)([CH3:9])[CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6].C(=O)([O-])[O-].[H][H]>CCO.C(Cl)Cl.[Pd]>[CH3:1][C:2]([NH2:10])([CH2:3][CH2:4][S:5]([CH3:8])(=[O:7])=[O:6])[CH3:9]
Reactant: CC(C)(CCS(C)(=O)=O)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(N)CCS(C)(=O)=O
Yield: 92 %

Procedure:
At RT, Pd/C (1.262 g of 10% wt., 10.65 mmol) was added to a solution of 3-methyl-1-(methylsulfonyl)-3-nitrobutane (338a, 2.08 g, 10.65 mmol) in EtOH (53.3 mL) and DCM (53.3 mL). The reaction mixture was placed under hydrogen (46 psi) in a carbonate jacketed reaction vessel at RT for 16 h when the pressure had reduced to ambient pressure. The reaction vessel was pressurized again to 50 psi hydrogen for 3 d when the pressure had reduced to 40 psi. The mixture was filtered through a pad of Celite, covered with sand, and washed with DCM then MeOH. The filtrate was distilled to first remove the DCM and MeOH before a white solid was observed; this was filtered, washed with DCM, and dried in vacuo to give 2-methyl-4-(methylsulfonyl)butan-2-amine (338b, 1.62 g, 9.80 mmol, 92% yield) as a crystalline white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.00 (d, J=17.21 Hz, 1H) 2.00 (t, J=4.11 Hz, 1H) 3.02 (s, 3H) 3.29 (d, J=17.21 Hz, 1H) 3.29 (t, J=4.50 Hz, 1H) 8.20 (br. s., 2H). MS (ESI, pos. ion) m/z: 166.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[Br:19])=[O:11].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>>[Br:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]1[CH2:2][NH:1][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1)=[O:11]
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@H](C)[C@@H]2CN)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example 11 starting with rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(2-bromo-5-methylphenyl)methanone and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 470, 472, [M]+, [M+2]+.